Heterocyclic aromatic compounds useful as growth hormone secretagogues

ABSTRACT

Novel heterocyclic aromatic compounds are provided that are useful in stimulating endogenous production or release of growth hormone, said compounds having the general structure of formula I  
                 
 
wherein R 1 , R 1 ′, R 2 , R 3 , R 4 , Xa, Y, Z and n are as described herein. 
The compounds provided herein are useful in treating obesity, osteoporosis (improving bone density) and in improving muscle mass and muscle strength.

RELATED APPLICATIONS

This application is a Divisional of co-pending U.S. patent applicationSer. No. 10/653,410, filed Sep. 2, 2003 that claims priority benefitunder Title 35 § 119(e) of U.S. provisional Application Nos. 60/408,099,filed Sep. 4, 2002, and 60/491,645, filed Jul. 31, 2003, the contents ofwhich are herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to novel heterocyclic aromatic compoundswhich stimulate endogenous production and/or release of growth hormone.Further, the present invention relates to methods for using suchcompounds and to pharmaceutical compositions containing such compounds.

BACKGROUND OF THE INVENTION

Growth hormone is important not only for linear body growth, but is alsoimportant for the maintenance of body composition, metabolism and heartfunction in adult life. In fact, treatment with growth hormone isemployed in both adults and children suffering from growth hormonedeficiency. Treatment with growth hormone has been shown to reduce bodyfat, increase fat-free mass, increase muscle strength, improve bone massand well-being. These beneficial effects associated with growth hormonetreatment suggest that growth hormone treatment may further be usefulfor the treatment of osteoporosis, frailty in the elderly, complicatedfracture, cardiomyopathy, obesity and some nitrogen-wasting conditionsresulting from, for example, AIDS, chronic dialysis, catabolic diseaseand glucocorticoid treatment. Johan Svensson, Exp. Opin. Ther. Patents,2000 10(7) 1071-1080; Ankersen et al., DDT, 1999, 4(11) 497-506.Moreover, growth hormone therapy is also been explored with a viewtowards reversing changes associated with aging.

Current methods for administering growth hormone are invasive in thatsynthetic growth hormone must be administered by daily injection.Therefore, if an orally administered secretagogue could be introducedthat is safe, efficacious, well tolerated, it would provide anattractive treatment alternative to current growth hormone treatment.

Growth hormone secretagogues are synthetically produced peptides andnon-peptides that stimulate the endogenous production and/or release ofgrowth hormone by acting on one or more specific receptors at bothpituitary and hypothalamic levels. Accordingly, orally active growthhormone secretagogues could offer attractive alternatives to traditionalgrowth hormone therapy, thus providing a more convenient means to treata wider array of diseases or disorders associated with growth hormonelevels in patient circulation.

SUMMARY OF THE INVENTION

In accordance with the present invention, novel heterocyclic aromaticcompounds are provided that have the general structure of formula I

wherein

Xa is 2 to 4 fused or spiro cycloalkyl, heterocycle, aryl or heteroarylrings, wherein one or more of said rings may optionally be substitutedwith one to five substituents selected from the group consisting of Raand Rb;

R₁ is a substituted or unsubstituted functional group selected from thegroup consisting of alkyl, aryl, alkenyl, alkynyl, arylalkyl,cycloalkyl, heterocycle, alkoxyalkyl, arylalcyloxyalkyl, aryloxyalkyl,heteroaryl, cycloalkylalkoxyalkyl, heteroarylalkoxy, heteroarylalkyl,heterocycloalkyl and heterocycloalkyl;

R₂, R₃ and R₄ are each independently a substituted or unsubstitutedfunctional group selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heterocycle, alkoxyalkyl,arylalkyloxyalkyl, aryloxyalkyl, heteroaryl, cycloalkylalkoxyalkyl,heteroarylalkyl and hetercycloalkyl, or R₃ and R₄ taken together canform a 3 to 8 membered cycloalkyl or heterocyclic ring, or one or moreof R₃ and R₄ can be taken together with one or more of Y and Z to form amono- or bicyclic cycloalkyl or heterocyclic ring;

R₁′ is a substituted or unsubstituted functional group selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, heterocycle, aryl andheteroaryl;

Y is a linking group selected from the group consisting of alkylene,alkenylene, alkynylene, arylene and heteroarylene, said linking groupmay optionally be substituted with one or more functional groupsselected from the group consisting of alkyl, aryl, cycloalkyl,heterocycle, alkoxyalkyl, heteroaryl, arylalkyl, arylalkyloxyalkyl,aryloxyalkyl, cycloalkylalkoxyalkyl, heteroarylalkyl andheterocycloalkyl, halogen, —OR₅, —OC(O)R₅, —CF₃, —OCF₃, —N(R₅)C(O)R₅′and —NR₅R₅′;

R₅ and R₅′ for each occurrence are each independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, heterocycle and aryl,wherein R₅ and R₅′ for each occurrence may optionally be substitutedwith one or more Rb; Ra and Rb for each occurrence are eachindependently selected from the group consisting of alkyl, alkenyl,alkynyl, halogen, cyano, carbonyl, —CN, aryl, arylalkyl, arylalkenyl,arylalkynyl, cycloalkyl, alkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl,heterocycle, heteroaryl, heteroarylalkyl, —OR₂, —NR₅R₅′, —CF₃, —SO₂R₆,—SO₂NR₆R₆′, —(CH₂)_(m)R₈ and R₉;

R₆ and R₆′ for each occurrence are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylthioalkyl,alkoxyalkyl, aryl, arylalkyl, heterocycle, heteroaryl, heteroarylalkyl,heterocycloalkyl and cycloalkyl, wherein R₆ and R₆′ for each occurrencemay optionally be substituted with 1 to 3 substituents selected from thegroup consisting of halogen, —OR₂, alkoxy, heterocycloalkyl,—NR₅C(O)NR₅R₅′, —C(O)NR₅R₅′, —NR₅C(O)R₅′, —CN, —NR₅SO₂R₅′, —OC(O)R₅,—SO₂NR₅R₅′, —SOR₇, —COOH and —C(O)OR₇, or R₆ and R₆′ taken together canbe cyclized to form —(CH₂)_(q)X(CH₂)_(s)—;

R₇ for each occurrence is independently selected from the groupconsisting of C₁ to C₆ alkyl, aryl and heteroaryl, wherein R₇ mayoptionally be substituted with —(CH₂)_(w)OH;

R₈ is selected from the group consisting of alkoxy, alkoxycarbonyl,—C(O)NR₆R₆′, —NR₅R₅′, —C(O)R₆, —NR₅C(O)NR₅R₅′ and —N-heteroaryl;

R₉ is selected from the group consisting of heterocycloalkyl,heteroaryl, —CN, —(CH₂)_(p)N(R₆)C(O)R₆′, —(CH₂)_(p)CN,—(CH₂)_(p)N(R₆)C(O)OR₆′, —(CH₂)_(p)N(R₆)C(O)NR₆R₆′,—(CH₂)_(p)N(R₆)SO₂R₆, —(CH₂)_(p)C(O)NR₆R₆′, —(CH₂)_(p)C(O)OR₆,—(CH₂)_(p)OC(O)OR₆, —(CH₂)_(p)OC(O)R₆, —(CH₂)_(p)OC(O)NR₆R₆′,—(CH₂)_(p)N(R₆)SO₂NR₆R₆′, —(CH₂)_(p)OR₆,—(CH₂)_(p)OC(O)N(R₆)(CH₂)_(m)OH—(CH₂)_(p)SOR₆ and—(CH₂)_(p)OCH₂C(O)N(R₆)(CH₂)_(m)OH;

X is selected from the group consisting of —CR₅R₅′—, —O—, —S—, —SO—,—SO₂—, —NC(O)OR₇—, —NC(O)NR₅— and —NR₅—;

Z is nitrogen;

m is an integer between 1 and 6;

n is an integer from 1 to 6;

p is an integer from 0 to 5;

w is an integer between 0 and 5; and

q and s are each independently an integer between 1 and 3, with theproviso that R₅, R₅′, R₆ or R₆′ cannot be hydrogen when either isconnected to a carbonyl group (e.g., —C(O)R₆) or sulfone group (e.g.,—SO₂R₆).

The definition of formula I above is inclusive of all prodrugs, prodrugesters, stereoisomers and pharmaceutically acceptable salts of formulaI.

Compounds of formula I demonstrate activity as growth hormonesecretagogues, that is they stimulate endogenous production and/orrelease of growth hormone and are useful in the treatment of diseases ordisorders associated with growth hormone levels, such as those diseasesor disorders disclosed herein.

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds and for methods ofusing such compounds. In particular, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound of formula I, alone or in combination with apharmaceutically acceptable carrier.

Moreover, in accordance with the present invention, a method is providedfor increasing levels of endogenous growth hormone or increasing theendogenous production or release of growth hormone, wherein atherapeutically effective amount of a compound of formula I isadministered to a mammalian, e.g., human, patient in need of treatment.

Furthermore, in accordance with the present invention, a method isprovided for preventing or treating diseases or disorders associatedwith mammialian growth hormone levels, such as described herein, whereina therapeutically effective amount of a compound of formula I isadministered to a mammalian, i.e., human, patient in need of treatment.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s) active in the therapeutic areas described herein.

Further, the present invention provides a method for preventing,inhibiting or treating the diseases as defined above and hereinafter,wherein a therapeutically effective amount of a combination of acompound of formula I and another compound of formula I and/or at leastone other type of therapeutic agent, is administered to a mammalian,i.e., human patient in need of treatment.

Preferred are compounds of formula I wherein Xa has the structure

wherein

Q₁ and Q₂ are each independently a cycloalkyl, heterocyclic, aryl orheteroaryl ring, wherein Q₁ may be substituted with 1 to foursubstituents selected from the group consisting of Ra and Rb, and Q₂ maybe substituted with 1 to four substituents selected from the groupconsisting of Ra, Rb and Q₃;

Q₃ is a 3 to 8 membered fused or spiral cycloalkyl, heterocyclic, arylor heteroaryl ring, wherein Q₃ may optionally be substituted with 1 to 5substituents selected from the group consisting of Ra, Rb and Q₄; and

Q₄ is a 3 to 8 membered fused or spiral cycloalkyl, heterocyclic, arylor heteroaryl ring, wherein Q₄ may optionally be substituted with 1 to 5substituents selected from the group consisting of Ra and Rb;

A is N or CR₁₁;

B is N or CR₁₁; and

R₁₁ is H or a bond.

Further embodiments include compounds of formula I wherein Xa has thestructure

Although the preferred Xa structures disclosed above illustrate one ormore Ra and/or Rb substituents on any particular cycloalkyl, aryl,heteroaryl or heterocycle ring, the preferred Xa structures are notlimited to the specific Ra/Rb substitution illustrated above, nor is anRa and/or Rb group needed. Rather, the presence of the Rb and/or Rasubstituents in the preferred Xa structures, the subsequent Schemes andthe claims hereafter, indicate that one or more Ra/Rb group(s) mayoptionally be attached at any available position of attachment upon thering to which an Rb/Rb group is associated. Therefore, even though thepreferred Xa structures, Schemes and claims hereinafter may reference aparticular embodiment, it should be understood that various othermodifications, such as the substitution of one or more Rb and/or Ragroups, or other modifications and therapeutically equivalent compoundsknown to those skilled in the art, may be employed within the scope andspirit of the compounds claimed herein.

Preferred are compounds of formula I wherein when Ra or Rb are R₉, R₆ isheterocycle or alkyl, optionally substituted with hydroxyl or halogen.

Preferred are compounds of formula I wherein when Ra or Rb are R₉, R₆and R₆′ are independently hydrogen, alkyl, or cycloalkyl, where thealkyl or cycloalkyl is optionally substituted with —C(O)OR₇ or—C(O)NR₅R₅′, or R₆ and R₆′ taken together can be cyclized to form—(CH₂)_(q)X(CH₂)_(s)—.

Also preferred are compounds of formula I wherein when Ra or Rb are R₉,R₉ is (CH₂)_(p)C(O)OR₆, (CH₂)_(p)OC(O)R₆, or(CH₂)_(p)OC(O)N(R₆)(CH₂)_(m)OH.

Also preferred are compounds of formula I wherein R₉ is—(CH₂)_(p)N(R₆)C(O)OR₆′, —(CH₂)_(p)N(R₆)C(O)NR₆R₆′, or(CH₂)_(p)OC(O)NR₆R₆′, where R₆ and R₆′ are independently hydrogen oralkyl, where the alkyl is optionally substituted with —C(O)NR₅R₅′, whereR₅ and R₅′ are independently hydrogen or alkyl.

Further preferred embodiments include compounds of formula I having thestructure:

Additional preferred embodiments include compounds of formula I havingthe structure:

The compounds of this invention all have at least one asymmetric centeras noted by the asterisk in structural formula I. Additional asymmetriccenters may be present on the molecule depending upon the nature of thevarious substituents on the molecule. Each such asymmetric center willproduce two optical isomers and it is intended that all such opticalisomers, as separated, pure or partially purified optical isomers orracemic mixtures thereof, be included within spirit and scope of thepresent invention. In the case of the asymmetric center represented bythe asterisk in formula I, the more active and thus more preferredconfiguration is R as determined by the R/S rules. Isomers may beseparated by conventional methods, for example, chromatographic orfractional crystallization.

DETAILED DESCRIPTION OF THE INVENTION

The following abbreviations are employed herein:

-   Boc=tert-butoxycarbonyl-   CBZ=benzyloxycarbonyl (or carbobenzoxy)-   DIBAL=diisobutylaluminum hydride-   DMAP=4-(dimethylamino)pyridine-   DMF=N,N-dimethylformamide-   EDAC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   EtOAc=ethyl acetate-   HOBT=hydroxybenztriazole-   HPLC=high performance liquid chromatography-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS or Mass Spec=mass spectrometry-   Pd/C=palladium on activated charcoal-   TFA=trifluoroacetic acid-   YMC=trademark of YMC Co, Ltd., Kyoto, Japan-   g=gram(s)-   h or hr=hour(s)-   min=minute(s)-   ml=milliliter-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   nM=nanomolar-   r.t.=room temperature-   Et=ethyl-   i-Pr=isopropyl-   Me=methyl

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

Unless otherwise indicated, the term “alkyl” as employed herein alone oras part of another group includes both straight and branched chainhydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons,more preferably 1 to 6 carbons, in the normal chain, such as methyl,ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl,isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl,nonyl, decyl, undecyl, dodecyl, the various branched chain isomersthereof, and the like. Further, alkyl groups, as defined herein, mayoptionally be substituted on any available carbon atom with one or morefunctional groups commonly attached to such chains, such as, but notlimited to alkyl, aryl, alkenyl, alkynyl, hydroxy, arylalkyl,cycloalkyl, cycloalkylalkyl, alkoxy, arylalkyloxy, alkanoyl, amino,halo, thio, cyano, carboxyl, carbonyl

amino, amido, haloaryl, CF₃, OCF₃, aryloxy, heteroaryl,cycloalkylalkoxyalkyl, cycloheteroalkyl and the like to form alkylgroups such as trifluoro methyl, 3-hydroxyhexyl, 2-carboxypropyl,2-fluoroethyl, carboxymethyl, cyanobutyl and the like.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl andtricyclic alkyl, containing a total of 3 to 20 carbons forming therings, preferably 4 to 10 carbons, forming the ring and which may befused to 1 aromatic ring as described for aryl, which includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 3substituents as defined above for alkyl.

The term “aryl” as employed herein alone or as part of another grouprefers to monocyclic and bicyclic aromatic groups containing 6 to 10carbons in the ring portion (such as phenyl or naphthyl) and mayoptionally include one to three additional rings fused to “aryl” (suchas aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and may beoptionally substituted through any available carbon atoms with 1 or moregroups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy,haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl,cycloalkylalkyl, fluorenyl, cycloheteroalkyl, cycloheteroalkylalkyl,aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy,arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl,heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, oxo, cyano, amino,substituted amino wherein the amino includes 1 or 2 substituents (whichare alkyl, aryl or any of the other aryl compounds mentioned in thedefinitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl,alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy,arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl, or anyof alkyl substituents as set out above.

The term “arylalkyl” as used herein alone or as part of another grouprefers to alkyl groups as defined above having an aryl substituent, suchas benzyl, phenethyl or naphthylpropyl, wherein said aryl and/or alkylgroups may optionally be substituted as defined above.

The term “alkoxy” or “aryloxy” as employed herein alone or as part ofanother group includes an alkyl or aryl group as defined above linkedthrough an oxygen atom.

Unless otherwise indicated, the term “alkenyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 3 to 12 carbons, and morepreferably 2 to 6 carbons in the normal chain, which include one or moredouble bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl,2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl,4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may beoptionally substituted with one or more functional groups as definedabove for alkyl.

Unless otherwise indicated, the term “alkynyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons and morepreferably 2 to 8 carbons in the normal chain, which include one or moretriple bonds in the normal chain, such as 2-propynyl, 3-butynyl,2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl,4-dodecynyl and the like, and which may be optionally substituted withone or more functional groups as defined above for alkyl.

The term “alkylene” as employed herein alone or as part of another grouprefers to alkyl linking groups above having single bonds for attachmentto other groups at two different carbon atoms and may optionally besubstituted as defined above for “alkyl”.

The terms “alkenylene” and “alkynylene” as employed herein alone or aspart of another group refer to alkenyl and alkynyl linking groups,having single bonds for attachment at two different carbon atoms and mayoptionally be substituted as defined above for “alkyl”. The term“halogen” or “halo” as used herein alone or as part of another grouprefers to chlorine, bromine, fluorine and iodine.

The term “heteroaryl” as used herein refers to a 5-, 6- or 7-memberedaromatic heterocyclic ring which contains one or more heteroatomsselected from nitrogen, sulfur, oxygen and/or a SO or SO₂ group. Suchrings may be fused to another cycloalkyl, cycloheteroalkyl, aryl orheteroaryl ring and include possible N-oxides. Optionally a heteroarylgroup may be substituted with one or more functional groups commonlyattached to such chains, such as those described for alkyl.

The term “heterocyclo”, “heterocycle” or “heterocyclic”, as used herein,represents an unsubstituted or substituted stable 4-, 5-, 6- or7-membered monocyclic ring system which may be saturated or unsaturated,and which consists of carbon atoms and from one to four heteroatomsselected from N, O, S and or a SO or SO₂ group, wherein the nitrogen andsulfur heteroatoms may optionally be oxidized, and the nitrogenheteroatom may optionally be quaternized. The heterocyclic ring may beattached at any heteroatom or carbon atom which results in the creationof a stable structure. Examples of such heterocyclic groups include, butis not limited to, piperidinyl, piperazinyl, oxopiperazinyl,oxopiperidinyl and oxadiazolyl. Optionally a heterocyclo group may besubstituted with one or more functional groups, such as those describedfor alkyl.

The term “heterocycloalkyl” or “heteroarylalkyl” as used herein alone oras part of another group refers to a heterocyclo or heteroaryl grouprespectively, linked through an alkyl group.

The term “alkoxyalkyl” or “aryloxyalkyl” as used herein alone or as partof another group refers to a alkoxy or aryloxy group respectively,linked through an alkyl group.

The term “heteroarylalkoxy” as used herein alone or as part of anothergroup refers to a heteroaryl group linked through an alkoxy group.

As used herein alone or as part of another group, the term“cycloalkylalkoxyalkyl” and “arylalkyloxyalkyl” refers to a cycloalkylgroup and an aryl group respectively, linked through an alkoxy group,that is in turn linked through an alkyl group.

The term “arylene” or “heteroarylene” as used herein alone or as part ofanother group, refers to a alkylene, alkenylene or alkynylene linkinggroup as defined above, wherein said alkylene, alkenylene or alkynylenelinking group contains an aryl (Ar) or heteroaryl (Het) group in thecarbon chain. Examples include, but are not limited to—(CH₂)₂—Ar—(CH₂)₂— or —(CH₂)₂-Het-(CH₂)₂—.

The term “carbonyl,” as used herein, refers to a —C(O)— group or whenreferred to as a possible substitutent, refers to a

group attached to any available carbon atom with in the functional groupor linking group being substituted.

The term “phenoxy” as used herin, refers to a phenyl substituent linkedthrough and oxygen atom. Optionally the phenyl ring porton a phenoxygroup may be substituted with one or more functional groups, such asdescribed for aryl.

An administration of a therapeutic agent of the invention includesadministration of a therapeutically effective amount of the agent of theinvention. The term “therapeutically effective amount” as used hereinrefers to an amount of a therapeutic agent to treat or prevent acondition treatable by administration of a composition of the invention.That amount is the amount sufficient to exhibit a detectable therapeuticor preventative or ameliorative effect. The effect may include, forexample, treatment or prevention of the conditions listed herein. Theprecise effective amount for a subject will depend upon the subject'ssize and health, the nature and extent of the condition being treated,recommendations of the treating physician, and the therapeutics orcombination of therapeutics selected for administration. Thus, it is notuseful to specify an exact effective amount in advance.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

The term “prodrug esters” as employed herein includes esters andcarbonates formed by reacting one or more hydroxyls of compounds offormula I with alkyl, alkoxy, or aryl substituted acylating agentsemploying procedures known to those skilled in the art to generateacetates, pivalates, methylcarbonates, benzoates and the like.

Various forms of prodrugs are well known in the art and are describedin:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch.31, (Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); and

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson andH. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers,1991). Said references are incorporated herein by reference.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic techniques or fractional crystallization.

The pharmaceutically acceptable salts of the compounds of formula I ofthe invention include alkali metal salts such as lithium, sodium orpotassium, alkaline earth metal salts such as calcium or magnesium, aswell as zinc or aluminum and other cations such as ammonium, choline,diethanolamine, ethylenediamine, t-butylamine, t-octylamine,dehydroabietylamine, as well as pharmaceutically acceptable anions suchas chloride, bromide, iodide, tartrate, acetate, methanesulfonate,maleate, succinate, glutarate, stearate and salts of naturally occurringamino acids such as arginine, lysine, alanine and the like, and prodrugesters thereof.

General Synthetic Schemes

The compounds of the present invention may be prepared according to thefollowing general synthetic reaction schemes as well as relevantpublished literature procedures that may be used by one skilled in theart. Exemplary reagents, procedures and conditions for these reactionsappear hereinafter and in the working examples. Starting materials arecommercially available or can be readily prepared by one of ordinaryskill in the art using known methods. Unless otherwise specified thevarious substituents of the compounds are defined in the same manner asthe formula I.

High Speed Analoging (HSA) may be employed in the preparation ofcompounds, for example, where the intermediates possess an amineposition or activated aromatic position, such as the halogenated Q₁ andQ₂.

Scheme I

Scheme I describes a general synthetic sequence for the preparation ofthe compounds of formula I. During the preparation of compounds offormula I, one or more protecting groups might be used, reactionconditions for protection and deprotection may be found in the‘Protective Groups in Organic Synthesis” Greene et al., John Wiley andSons Inc, 1991, or other methods used by one of ordinary skill in theart.

Compounds of formula I can be prepared from a compound of formula II andamine XXXII using an appropriate carboxylic acid activating reagent inan inert solvent. Exemplary carboxylic acid activating agents includeisobutylchloroformate, carbonyldiimidazole, dicyclohexylcarbodiimide,pentofluorophenol trifluoroacetate, or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Exemplary inert solventsinclude ethers, dioxane, tetrahydrofuran, N,N-dimethylformamide,acetonitrile, or methylene chloride. If R₃ and/or R₄ are an amineprotecting group, such as Boc-, CBZ or Trityl, they will be deprotectedto afford the final products. Reaction conditions for deprotection maybe founds in the ‘Protective Groups in Organic Synthesis” Greene et al.,John Wiley and Sons Inc, 1991, or other methods used by one of ordinaryskill in the art.

Compound XXXII can be prepared by the deprotection of compound IV wherePG is an appropriate amino protecting group such as Boc-, CBZ or Trityl,etc. Exemplary deprotection reagents for Boc- are hydrogen chloride indioxane, TFA in dichloromethane, etc.; exemplary deprotection for CBZ iscatalytic hydrogenation, exemplary deprotection for Trityl is hydrogenchloride in acetone or tetrahydrofuran.

Compound XXXIII can be prepared from compound XXXIV. When

is a hydroxyl group in compound XXXIV, it can be converted to an azidegroup followed by reduction to give the amino group in compound XXXIII.(for an example, see Lautens et al, J. Org. Chem. (1997) 62, 5246-5247).When

is a carbonyl group, it can be reduced to a hydroxyl group thenconverted to the amino group in compound XXXIII. Alternatively, it canbe converted to an O-methyl oxime, then followed by reduction to givethe amino group in compound XXXIII. Reduction of O-methyl oxime to aminecan be carried out with borane tetrahydrofuran complex or other methodsused by one of ordinary skill in the art.

Compound XXXIV can be prepared from reaction of compound XXXVI andcompound XXXV. Compounds XXXV [Y═H, SPh, Cl, NMe(OMe)] can be preparedby one of the ordinary skill in the art. Compounds XXXVI (M=Li, MgBr,MgCl, ZnBr, ZnI) is an organometalic intermediate, which can be preparedfrom an appropriate precursor (X═B, I, Cl). or other methods used by oneof ordinary skill in the art. Organic zinc reagents can be prepared viatreatment of arylbromide or aryliodide with Rieke®zinc metal asdescribed in J. Org. Chem. (1991), 56, 1445 or Tetrahedron (1997), 53,1925. Alternatively, it can also be prepared via treatment ofarylbromide or aryliodide with n-BuLi or tert-BuLi followed by additionof zinc bromide or zinc iodide.

Compounds of the formula Ia can be prepared via the aminolysis of acompound of formula II using an appropriate carboxylic acid activatingreagent and amine III in an inert solvent. Exemplary carboxylic acidactivating agents include isobutylchloroformate, carbonyldiimidazole,dicyclohexylcarbodiimide, pentofluorophenol trifluoroacetate, or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Exemplary inert solventsinclude ethers, including tetrahydrofuran and dioxane,N,N-dimethylformamide, acetonitrile, or methylene chloride. If R₃ and/orR₄ are an amine-protecting group, such as Boc-, or CBZ, they will bedeprotected to afford the final products. Deprotections are done by oneof ordinary skill in the art as described in the following.

Compound III can be prepared by the deprotection of compound IV where Gis an appropriate amino protecting group such as Boc-, CBZ, etc., ascommonly used by one of ordinary skill in the art. Exemplarydeprotection reagents for Boc- are hydrogen chloride in dioxane, TFA,etc; exemplary deprotection for CBZ is catalytic hydrogenation.

Compound IV can be prepared from compound V via a dehydrating process.Exemplary dehydrating agents include POCl₃, SOCl₂, HCl, HOAc andMitsunobu reactions.

Compound V can be prepared from compounds VII via aminolysis using anappropriate carboxylic acid activating reagent and amine VI in an inertsolvent. Exemplary carboxylic acid activating agents includeisobutylchloroformate, carbonyldiimidazole, dicyclohexylcarbodiimide,pentofluorophenol trifluoroacetate, or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Exemplary inert solventsinclude ethers, including tetrahydrofuran and dioxane,N,N-dimethylformamide, acetonitrile, or methylene chloride.

Although compound VI discloses two Rb substituents on the pyridine ring,the schemes are not limited to a single Rb group, nor is an Rb groupneeded. Rather, the presence of the Rb substituents in Scheme Ia and thesubsequent Schemes hereafter, indicate that one or more Rb groups mayoptionally be attached at any available position of attachment upon thering to which the Rb group is associated. Therefore, even though SchemeIIa and the Schemes hereinafter may reference a particular embodiment,it should be understood that various other modifications, such as thesubstitution of one or more Rb groups, or other modifications known tothose skilled in the art, may be employed within the scope and spirit ofthe general synthetic schemes herein.

Alternately, compound V can be prepared by the condensation of IX andVIII (where X is a leaving group such as a halogen) in an inert solventat elevated temperatures. Exemplary inert solvents include DMF, THF,dioxane, acetonitrile, pyridine, and inert alcohol such as ethanol.Exemplary temperatures can range from 40 to 150° C.

Compound IX can be prepared by the hydrazinolysis of X via proceduresused by one of ordinary skill in the art.

Alternately, compound IV can be prepared by the hydrazinolysis ofcompound XI in an inert solvent at elevated temperature. Exemplary inertsolvents include hydrazine, HOAc, THF, dioxane, pyridine and inertalcohol such as ethanol. Exemplary temperatures can range from 40 to150° C.

Compound XI can be prepared by the condensation of XII and VII via anappropriate carboxylic acid activating agent in an inert solvent.Exemplary carboxylic acid activating agents includeisobutylchloroformate, carbonyldiimidazole, dicyclohexylcarbodiimide,pentofluorophenol trifluoroacetate, or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Exemplary inert solventsinclude ethers, including tetrahydrofuran and dioxane,N,N-dimethylformamide, acetonitrile, or methylene chloride.

Scheme IIIa describes a general synthetic sequence for the preparationof the compounds of formula XIII (where E can be CH₂, CRaRb, NRa, O, S,SO₂, SO, CO, C(O)O, C(O)NRa, and m and n can independently be an integerfrom 0 to 6, with the caveat that m and n together form a 5-12 memberedring structure.

Compounds of formula XIII can be prepared via the aminolysis of acompound of formula II using an appropriate carboxylic acid activatingreagent and amine XIV in an inert solvent. Exemplary carboxylic acidactivating agents include isobutylchloroformate, carbonyldiimidazole,dicyclohexylcarbodiimide, pentofluorophenol trifluoroacetate, or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Exemplary inert solventsinclude ethers, including tetrahydrofuran and dioxane,N,N-dimethylformamide, acetonitrile, or methylene chloride. If R₃ and/orR₄ are an amine-protecting group, such as Boc-, or CBZ, they will bedeprotected to afford the final products. Deprotections are done by oneof ordinary skill in the art as described in the following.

Compound XIV can be prepared by the deprotection of compound XV where PGis an appropriate amino protecting group such as Boc-, CBZ, etc. used byone of ordinary skill in the art. Exemplary deprotection reagents forBoc- are hydrogen chloride in dioxane, TFA, etc; exemplary deprotectionfor CBZ is catalytic hydrogenation.

Compound XVI can be prepared from compound X via a dehydratingconditions in protonic and aprotic solvents. Dehydrating conditions canbe exemplified by using protonic solvent along or by using combinationswith dehydrating agents include HOAc, PPTS or by using Mitsunobureactions in the inert solvents.

Compound XVI can be prepared from coupling compounds IX and compoundXVII in inert solvent.

Schemes IVa-IVc can be carried out using similar general procedures asdescribed for Scheme IIIa, where intermediates XVIIIa, XVIIIb and XVIIIcare utilized in place of intermediate XVIII. m and n can independentlybe an integer from 0 to 5, with the caveat that m and n together form a6-12 membered ring structure.

Compounds of formula XIX can be prepared from a compound of formula IIand amine XX using an appropriate carboxylic acid activating reagent inan inert solvent. Exemplary carboxylic acid activating agents includeisobutylchloroformate, carbonyldiimidazole, dicyclohexylcarbodiimide,pentofluorophenol trifluoroacetate or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Exemplary inert solventsinclude ethers, dioxane, tetrahydrofuran, N,N-dimethylformamide,acetonitrile or methylene chloride. If R₃ and/or R₄ are anamine-protecting group, such as Boc-, CBZ or Trityl, they will bedeprotected to afford the final products. Reaction conditions fordeprotection may be founds in the ‘Protective Groups in OrganicSynthesis” Greene et al., John Wiley and Sons Inc, 1991, or othermethods used by one of ordinary skill in the art.

Compound XX can be prepared by the deprotection of compound XXI where PGis an appropriate amino protecting group such as Boc-, CBZ or Trityl,etc. Reaction conditions for deprotection may be founds in the‘Protective Groups in Organic Synthesis” Greene et al., John Wiley andSons Inc, 1991, or other methods used by one of ordinary skill in theart. Exemplary deprotection reagents for Boc- are hydrogen chloride indioxane, TFA in dichloromethane, etc.; exemplary deprotection for CBZ iscatalytic hydrogenation, exemplary deprotection for Trityl is hydrogenchloride in acetone or tetrahydrofuran.

Compound XXI can be prepared from compound XXII (X═Cl or F). CompoundXXII first react with hydroxyamine to give an oxime intermediate, thenfollowed by cyclization under basic condition or other methods used byone of ordinary skill in the art.

Compound XXII can be prepared from compound XXIII via treatment ofappropriate organic zinc reagents in an inert solvent such as ethers,tetrahydrofuran or toluene. Organic zinc reagents can be prepared viatreatment of arylbromide or aryliodide with Rieke® zinc metal asdescribed in J. Org. Chem. (1991), 56, 1445 or Tetrahedron (1997), 53,1925. Alternatively, it can also be prepared via treatment ofarylbromide or aryliodide with n-BuLi or tert-BuLi followed by additionof zinc bromide or zinc iodide.

Compounds XXIII can be prepared from a compound of formula VII and amercapto compound such as thiophenol using an appropriate carboxylicacid activating reagent in an inert solvent. Exemplary carboxylic acidactivating agents include isobutylchloroformate, carbonyldiimidazole,dicyclohexylcarbodiimide, pentofluorophenol trifluoroacetate, or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Exemplary inert solventsinclude ethers, dioxane, tetrahydrofuran, N,N-dimethylformamide,acetonitrile, or methylene chloride.

XXIV can be prepared from a compound of formula II and amine XX using anappropriate carboxylic acid activating reagent in an inert solvent.Exemplary carboxylic acid activating agents includeisobutylchloroformate, carbonyldiimidazole, dicyclohexylcarbodiimide,pentofluorophenol trifluoroacetate, or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Exemplary inert solventsinclude ethers, dioxane, tetrahydrofuran, N,N-dimethylformamide,acetonitrile, or methylene chloride. If R₃ and/or R₄ are anamine-protecting group, such as Boc-, CBZ or Trityl, they will bedeprotected to afford the final products. Reaction conditions fordeprotection may be founds in the ‘Protective Groups in OrganicSynthesis” Greene et al., John Wiley and Sons Inc, 1991, or other knownmethods used by one of ordinary skill in the art.

Compound XX can be prepared by the deprotection of compound XXI where PGis an appropriate amino protecting group such as Boc-, CBZ or Trityl,etc. Reaction conditions for deprotection may be founds in the‘Protective Groups in Organic Synthesis” Greene et al., John Wiley andSons Inc, 1991, or other known methods used by one of ordinary skill inthe art. Exemplary deprotection reagents for Boc- are hydrogen chloridein dioxane, TFA in dichloromethane, etc.; exemplary deprotection for CBZis catalytic hydrogenation, exemplary deprotection for Trityl ishydrogen chloride in acetone or tetrahydrofuran.

Compound XXI can be prepared from compound XXII (X═Cl or F). CompoundXXII first react with hydroxyamine to give an oxime intermediate, thenfollowed by cyclization under basic condition or other methods used byone of ordinary skill in the art.

Compound XXII can be prepared by reduction of azido compound XXVfollowed by protection of the resulting amine intermediate by an amineprotecting group such as Boc, CBz or Trityl, etc. Exemplary reductionreaction include hydrogenation or with triphenylphosphine in aqueoustetrahydrofuran. Reaction conditions for protection of the resultingamine intermediate may be founds in the ‘Protective Groups in OrganicSynthesis” Greene et al., John Wiley and Sons Inc, 1991, or othermethods used by one of ordinary skill in the art.

Compounds XXV can be prepared from a compound of formula XXVI in a twostep sequence or other known methods in the art. Treatment of compoundXXVI with bromine resulted in a α-bromoketone intermediate, which wasfollowed by treatment with azide ion such as sodium azide.

Compounds XXVI can be prepared from a compound of formula XXVII with anorganic metal reagent XXIXa or XXIXb.

Compound XXVII can be prepared from an acid XXVIII andN,O-dimethyl-amine hydrochloride using an appropriate carboxylic acidactivating reagent and base in an inert solvent. Exemplary carboxylicacid activating agents include isobutylchloroformate,carbonyldiimidazole, dicyclohexylcarbodiimide, pentofluorophenoltrifluoroacetate, or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.Exemplary inert solvents include ethers, dioxane, tetrahydrofuran,N,N-dimethylformamide, acetonitrile, or methylene chloride.Alternatively, acid XXVIII can be converted to the corresponding acidchloride using oxalyl chloride, thionyl chloride or other known methodsin the art. The resulting acid chloride can then reacted withN,O-dimethyl-amine hydrochloride in the presence of a base such astrimethylamine in an inert solvent.

Compound XXIXa is commonly known as Grignard reagents, and can beprepared by known methods used by one of ordinary skill in the art.

Compound XXIXb can be prepared by treatment of compound XXXb with MeLior n-BuLi or by known methods used by one of ordinary skill in the art.

Utilities and Combinations

A. Utilities

The growth hormone releasing compounds of formula I can be administeredto animals, including man, to release growth hormone in vivo. Forexample, the compounds can be administered to commercially importantanimals such as swine, cattle, sheep and the like to accelerate andincrease their rate and extent of growth, and to increase milkproduction in such animals.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, at least one of thecompounds of formula I in association with a pharmaceutical carrier ordiluent. Optionally, the active ingredient of the pharmaceuticalcompositions can comprise a growth promoting agent in addition to atleast one of the compounds of formula I or another composition whichexhibits a different activity, e.g., an antibiotic or otherpharmaceutically active material.

Growth promoting agents include, but are not limited to, TRH,diethylstilbesterol, theophylline, enkephalins, E series prostaglandins,compounds disclosed in U.S. Pat. No. 3,239,345, e.g., zeranol, andcompounds disclosed in U.S. Pat. No. 4,036,979, e.g., sulbenox orpeptides disclosed in U.S. Pat. No. 4,411,890.

A still further use of the disclosed compounds of formula I of theinvention is in combination with other growth hormone secretagogues suchas GHRP-6, GHRP-1 as described in U.S. Pat. No. 4,411,890; andpublications WO 89/07110 and WO 89/07111 and B-HT920 or growth hormonereleasing factor and its analogs or growth hormone and its analogs orsomatomedins including IGF-1 and IGF-2. A still further use of thedisclosed compounds of formula I of the invention is in combination withparathyroid hormone or bisphosphonates, such as MK-217 (alendronate), inthe treatment of osteoporosis.

A still further use of the disclosed compounds of formula I is incombination with estrogen, testosterone, a selective estrogen receptormodulator, such as tamoxifen or raloxifene, or a selective androgenreceptor modulator, such as disclosed in Edwards, J. P. et al., Bio.Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et al., J. Med.Chem., 42, 210-212 (1999), for the treatment of aspects of MetabolicSyndrome, maintenance of muscle strength and function in elderly humans,reversal or prevention of fraility in elderly humans, stimulation andincrease in muscle mass and muscle strength, attenuation of proteincatabolic response after a major operation or trauma; reducing cachexiaand protein loss due to chronic illness such as cancer or AIDS;improvement in muscle mobility, and maintenance of skin thickness.

A further use of the compounds of this invention is in combination withprogestin receptor agonists (“PRA”).

As is well known to those skilled in the art, the known and potentialuses of growth hormone are varied and multitudinous. Thus, theadministration of the compounds of this invention for purposes ofstimulating the release of endogenous growth hormone can have the sameeffects or uses as growth hormone itself.

To those skilled in the art, it is well known that the current andpotential uses of growth hormone are varied and multitudinous. Thus,compounds of formula I can be administered for purposes stimulatingrelease of endogenous growth hormone and would thus have similar effectsor uses as growth hormone itself. Compounds of formula I are useful forstimulation of growth hormone release (e.g., in the elderly);maintenance of muscle strength and function (e.g., in the elderly);reversal or prevention of fraility or age-related functional decline(“ARFD”) in the elderly; prevention of catabolic side effects ofglucocorticoids; prevention and treatment of osteoporosis; treatment ofchronic fatigue syndrome (CFS); treatment of acute fatigue syndrome andmuscle loss following election surgery; stimulation of the immunesystem, including improvement of immune response to vaccination;acceleration of wound healing; accelerating bone fracture repair (suchas accelerating the recovery of hip fracture patients); acceleratinghealing of complicated fractures, e.g. disctraction osteogenesis;acceleration of tooth repair or growth; maintenance of sensory function(e.g., hearing, sight, olefaction and taste); treatment of wastingsecondary to fractures; treatment of growth retardation; treatment ofgrowth retardation resulting from renal failure or insufficiency;treatment of cardiomyopathy; treatment of wasting in connection withchronic liver disease; treatment of thrombocytopenia; treatment ofgrowth retardation in connection with Crohn's disease; treatment ofshort bowel syndrome; treatment of irritable bowel syndrome; treatmentof inflammatory bowel disease; treatment of Crohn's disease andulcerative colits; treatment of wasting in connection with chronicobstructive pulmonary disease (COPD); treatment of complicationsassociated with transplantation; treatment of physiological shortstature including growth hormone deficient children and short statureassociated with chronic illness; treatment of obesity and growthretardation associated with obesity; treatment of anorexia (e.g.,associated with cachexia or aging); treatment of growth retardationassociated with the Prader-Willi syndrome and Turner's syndrome;increasing the growth rate of a patient having partial growth hormoneinsensitive syndrome; accelerating the recovery and reducinghospitalization of burn patients; treatment of intrauterine growthretardation, skeletal dysplasia, hypercortisolism and Cushing'ssyndrome; induction of pulsatile growth hormone release; replacement ofgrowth hormone in stressed patients; treatment ofosteochondrodysplasias; treatment of Noonan's syndrome; treatment ofschizophrenia; treatment of depression; improvement of cognitivefunction (e.g., treatment of dementia; treatment of Alzheimer's disease;treatment of delayed wound healing and psychosocial deprivation;treatment of catabolism in connection with pulmonary dysfunction andventilator dependency; treatment of cardiac dysfunction (e.g. associatedwith valvular disease, myocarial infarction, cardiac hypertrophy orcongestive heart failure); lowering blood pressure; protection againstventricular dysfunction or prevention of reperfusion events; treatmentof adults in chronic dialysis; reversal or slowing of the catabolicstate of aging; attenuation or reversal of protein catabolic responsesfollowing trauma (e.g., reversal of the catabolic state associated withsurgery, congestive heart failure, cardiac myopathy, burns, cancer, COPDetc.); reducing cachexia and protein loss due to chronic illness such ascancer or AIDS; treatment of hyperinsulinemia includingnesidioblastosis; adjuvant treatment for ovulation induction;stimulation of thymic development and prevention of the age-relateddecline of thymic function; treatment of immunosuppressed patients;treatment of sarcopenia; treatment of wasting in connection with AIDS;treatment of wasting in connection with multiple sclerosis or otherneurodegenerative disorders; improvement in muscle strength, mobility,maintenance of skin thickness; hair/nail growth; treatment of metabolichomeostasis and renal homeostasis (e.g., in the frail elderly);stimulation of osteoblasts, bone remodelling and cartilage growth;regulation of food intake; stimulation of the immune system in companionanimals and treatment of disorders of aging in companion animals;promoting growth in livestock; stimulation of wool growth in sheep;increasing milk production in livestock; treatment of insulin resistanceincluding NIDDM, in mammals (e.g. humans); treatment of insulinresistance in the heart; improvement of sleep quality and correction ofthe relative hyposomatotropism of senescence due to high increase in REMsleep and a decrease in REM latency; treatment of hypothermia; treatmentof frailty such as that associated with aging; treatment of congestiveheart failure; treatment of hip fractures; treatment of immunedeficiency in individuals with a depressed T4/T8 cell ratio; treatmentof lipodystrophy (e.g., in patients taking HIV or AIDS therapies such asprotease inhibitors); treatment of muscular atrophy (e.g., due tophysical inactivity, bed rest or reduced weight-bearing conditions);treatment of musculoskeletal impairment (e.g., in elderly); enhancingthe activity of protein kinase B (PKB); improvement of the overallpulmonary function; treatment of sleep disorders; and the treatment ofthe catabolic state of prolonged critical illness. The term treatment isalso intended to include prophylactic treatment.

In addition, the conditions, diseases, and maladies collectivelyreferenced to as “Syndrome X” or Metabolic Syndrome as detailed inJohannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997), may betreated employing the compounds of the invention.

B. Combinations

The compounds of the present invention may be employed alone or incombination with each other and/or other growth hormone secretagogues orother suitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-diabetic agents;anti-osteoporosous agents; anti-obesity agents; anti-inflammatoryagents; anti-anxiety agents; anti-depressants; anti-hypertensive agents;anti-platelet agents; anti-thrombotic and thrombolytic agents; cardiacglycosides; cholesterol/lipid lowering agents; mineralocorticoidreceptor antagonists; phospodiesterase inhibitors; protein tyrosinekinase inhibitors; thyroid mimetics (including thyroid receptorantagonists); anabolic agents; HIV or AIDS therapies; therapies usefulin the treatment of Alzheimer's disease and other cognitive disorders;therapies useful in the treatment of sleeping disorders;anti-proliferative agents; anti-tumor agents; and/or anti-ulcer andgastroesopheageal reflux disease agents.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include biguanides (e.g.metformin), glucosidase inhibitors (e.g. acarbose), insulins (includinginsulin secretagogues or insulin sensitizers), meglitinides (e.g.repaglinide), sulfonylureas (e.g., glimepiride, glyburide andglipizide), biguanide/glyburide combinations (e.g., glucovance),thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone),PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dualagonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein(aP2) such as those disclosed in U.S. Ser. No. 09/519,079 filed Mar. 6,2000 (attorney docket LA27), glucagon-like peptide-1 (GLP-1), anddipeptidyl peptidase IV (DP4) inhibitors.

Examples of suitable anti-osteoporosous agents for use in combinationwith the compounds of the present invention include alendronate,risedronate, raloxifene, calcitonin, non-steroidal progestin receptoragonists, RANK ligand agonists, calcium sensing receptor antagonists,TRAP inhibitors, selective estrogen receptor modulators (SERM), estrogenand AP-1 inhibitors;

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include aP2 inhibitors such as thosedisclosed in U.S. Ser. No. 09/519,079 filed Mar. 6, 2000 (attorneydocket LA27), PPAR gamma antagonists, PPAR delta agonists, and orlistat.

Examples of suitable antinflammatory agents for use in combination withthe compounds of the present invention include prednisone,dexamethasone, Enbrel, cyclooxygenase inhibitors (i.e., COX-1 and/orCOX-2 inhibitors such as NSAIDs, aspirin, indomethacin, ibuprofen,piroxicam, Naproxen, Celebrex, Vioxx), CTLA4-Ig agonists/antagonists,CD40 ligand antagonists, integrin antagonists, alpha4 beta7 integrinantagonists, cell adhesion inhibitors, interferon gamma antagonists,ICAM-1, tumor necrosis factor (TNF) antagonists (e.g., infliximab,OR1384), prostaglandin synthesis inhibitors, budesonide, clofazimine,CNI-1493, CD4 antagonists (e.g., priliximab), p38 mitogen-activatedprotein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKKinhibitors, and therapies for the treatment of irritable bowel syndrome(e.g., zelmac and Maxi-K openers such as those disclosed in U.S. Pat.No. 6,184,231 B1).

Example of suitable anti-anxiety agents for use in combination with thecompounds of the present invention include diazepam, lorazepam,buspirone, oxazepam, and hydroxyzine pamoate.

Examples of suitable anti-depressants for use in combination with thecompounds of the present invention include citalopram, fluoxetine,nefazodone, sertraline, and paroxetine.

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include beta adrenergicblockers, calcium channel blockers (L-type and T-type; e.g. diltiazem,verapamil, nifedipine, amlodipine and mybefradil), diruetics (e.g.,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists(e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), and nitrates.

Examples of suitable anti-platelet agents for use in combination withthe compounds of the present invention include GPIIb/IIIa blockers(e.g., abciximab, eptifibatide, tirofiban), P2Y12 antagonists (e.g.,clopidogrel, ticlopidine, CS-747), thromboxane receptor antagonists(e.g., ifetroban), aspirin, and PDE-III inhibitors (e.g., dipyridamole)with or without aspirin.

Examples of suitable cardiac glycosides for use in combination with thecompounds of the present invention include digitalis and ouabain.

Examples of suitable cholesterol/lipid lowering agents for use incombination with the compounds of the present invention include HMG-CoAreductase inhibitors (e.g., pravastatin lovastatin, atorvastatin,simvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin)and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)),squalene synthetase inhibitors, fibrates, bile acid sequestrants, ACATinhibitors, MTP inhibitors, lipooxygenase inhibitors, choesterolabsorption inhibitors, and cholesterol ester transfer protein inhibitors(e.g., CP-529414).

Examples of suitable mineralocorticoid receptor antagonists for use incombination with the compounds of the present invention includespironolactone and eplerinone.

Examples of suitable phospodiesterase inhibitiors for use in combinationwith the compounds of the present invention include PDEIII inhibitorssuch as cilostazol, and PDE V inhibitors such as sildenafil.

Examples of suitable thyroid mimetics for use in combination with thecompounds of the present invention include thyrotropin, polythyroid,KB-130015, and dronedarone.

Examples of suitable anabolic agents for use in combination with thecompounds of the present invention include testosterone and SARMs.

Examples of suitable HIV or AIDS therapies for use in combination withthe compounds of the present invention include indinavir sulfate,saquinavir, saquinavir mesylate, amprenavir, ritonavir, lopinavir,ritonavir/lopinavir combinations, lamivudine, zidovudine,lamivudine/zidovudine combinations, zalcitabine, didanosine, stavudine,and megestrol acetate.

Examples of suitable therapies for treatment of Alzheimer's disease andcognitive disorders for use in combination with the compounds of thepresent invention include donepezil, tacrine, revastigmine, 5HT6, gammasecretase inhibitors, beta secretase inhibitors, SK channel blockers,Maxi-K blockers, and KCNQs blockers.

Examples of suitable therapies for treatment of sleeping disorders foruse in combination with the compounds of the present invention includemelatonin analogs, melatonin receptor antagonists, ML1B agonists, andGABA/NMDA receptor antagonists.

Examples of suitable anti-proliferative agents for use in combinationwith the compounds of the present invention include cyclosporin A,taxol, FK 506, and adriamycin.

Examples of suitable anti-tumor agents for use in combination with thecompounds of the present invention include taxol, adriamycin,epothilones, cisplatin and carboplatin.

Compounds of the present invention may further be used in combinationwith nutritional supplements such as those described in U.S. Pat. No.5,179,080, especially in combination with whey protein or casin, aminoacids (such as leucine, branched amino acids and hydroxymethylbutyrate),triglycerides, vitamins (e.g., A, B6, B12, folate, C, D and E), minerals(e.g., selenium, magnesium, zinc, chromium, calcium and potassium),camitine, lipoic acid, creatine, and coenzyme Q-10.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

The compounds of the present invention are agents that are growthhormone secretagogues and can be administered to various mammalianspecies, such as monkeys, dogs, cats, rats, humans, etc., in need oftreatment. These agents can be administered systemically, such as orallyor parenterally.

The compounds of the invention can be incorporated in a conventionalsystemic dosage form, such as a tablet, capsule, elixir or injectableformulation. The above dosage forms will also include the necessaryphysiologically acceptable carrier material, excipient, lubricant,buffer, antibacterial, bulking agent (such as mannitol), anti-oxidants(ascorbic acid or sodium bisulfite) or the like. Oral dosage forms arepreferred, although parenteral, intranasal or aerosol forms are quitesatisfactory as well.

The dose administered must be carefully adjusted according to the age,weight, and condition of the patient, as well as the route ofadministration, dosage form and regimen, and the desired result. Ingeneral, the dosage forms described above may be administered in amountsfrom about 0.0001 to about 100 mg/kg or body weight or in an amountwithin the range from about 1 to about 1000 mg per day, preferably, fromabout 5 to about 500 mg per day in single or divided doses of one tofour times daily.

EXAMPLES

The following Examples represent preferred embodiments of the invention.All temperatures are in ° C. unless indicated otherwise.

General Experimental

Method A: The term HPLC refers to a Shimadzu high performance liquidchromatography using a 4 minute gradient of 0-100% solvent B[MeOH:H2O:0.2% H3PO4] with a 1 min. hold, an ultra violet (uv) detectorset at 220 nM and using a column (4.6×50 mm) packed with YMC C18 5micron resin.

A mixture of solvent A (10% MeOH/90% H₂O/0.2% TFA) and solvent B (90%MeOH/10% H2O/0.2% TFA) are used for preparative reverse phase HPLC in anautomated Shimadzu system. The preparative columns are packed with YMCODS C18 5 micron resin.

Method B: The term HPLC refers to a Shimadzu high performance liquidchromatography using an 8 minute gradient of 0-100% solvent B[acetonitrile:H2O:0.1% TFA] with a 3 min. hold, an ultra violet (uv)detector set at 220 nM, and using a column (4.6×75 mm) packed withZorbax C18 5 micron resin.

A mixture of solvent A (10% acetonitrile/90% H₂O/0.1% TFA) and solvent B(90% acetonitrile/10% H2O/0.1% TFA) are used for preparative reversephase HPLC in an automated Shimadzu system. The preparative columns arepacked with YMC ODS C18 5 micron resin.

Method C: The term HPLC refers to a Shimadzu high performance liquidchromatography using an 8 minute gradient of 0-100% solvent B[MeOH:H2O:0.2% H3PO4] with a 2 min. hold, an ultra violet (uv) detectorset at 220 nNM, and using a column (4.6×75 mm) packed with Zorbax C18 5micron resin.

The preparative column for the chiral preparative HPLC was packed withChiralpak AD 2 μM (5×50 cm) using Isopropyl alcohol and hexane as thesolvents.

Example 12-Amino-N-[1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-phenyl-propyl]-2-methyl-propionamide

To a THF (100 ml) solution of3-benzyloxy-2-tert-butoxycarbonylamino-propionic acid (20.0 g, 67.8mmol) was added N-methyl morpholine (11.2 ml, 101.7 mmol), followed bythe addition of iso-butyl chloroformate (11.1 ml, 74.mmol) dropwise. AWhite suspension was formed. This suspension was stirred at r.t. For 10min and then 5-bromo-pyridin-2-yl hydrazine (14.1 g, 74.6 mmol) wasadded in three portions. The resulting suspension was stirred at r.t.for 1 h and then the solvent was removed under reduced pressure until athick slurry was formed. Water was added and the suspension was stirredto ensure the solid was finely dispersed. The off-white solid wasfiltered and washed with NaOH (1N, 100 ml), water (100 ml) and HCl (1N,100 ml) and then water (200 ml) dried to give 1A (31.5 g, 100%).

To a THF (100 ml) solution of 1A (30 g, 64.3 mmol) was addedtriphenylphosphine (20.2 g, 77.2 mmol), and trimethylsilyl azide (10.2ml, 77.2 mmol). To this solution was added diethyl diazacarboxylate(DEAD, 15.2 ml, 96.5 mmol) in rapid drops. The solution became hot.After the addition was complete, the solution was allowed to stir atr.t. until all starting material was consumed (<2 h). The solvent wasremoved under reduced pressure to give 1B.

1B (64.3 mmol) was suspended in HCl-dioxane (160 ml, 4 MHCl in dioxane).The suspension was stirred at r.t. until all of the starting materialwas consumed. The suspension was concentrated to a thick slurry and thendiluted with THF (100 ml). The solid was collected by filtration andrinsed with excess CH₂Cl₂, diethyl ether, and dried to give 1C (24.5 g,99%).

To a THF (100 ml) solution of2-tert-butoxycarbonylamino-2-methyl-propionic acid (9.5 g, 47.9 mmol)was added EDAC (11.2 g, 58.8 mmol) and HOBT (8.0 g, 58.8 mmol), DMAP(4.8 g, 39.2 mmol), and (i-Pr)₂NEt (20.5 ml, 117.6 mmol). This solutionwas stirred at r.t. for 10 min before the addition of 1C (15 g, 39.2mmol). The reaction was completed in <1 h. The solvent was then removedunder reduced pressure and the residue was dissolved in EtOAc (200 ml).The organic solution was washed with water (200 ml), NaOH (0.5N, 200ml), HCl (0.5N, 200 ml), and water (200 ml). The organic layer was driedover Na₂SO₄ and concentrated to give a white solid 1D (20.0 g, 90%)

1D (1.0 g, 1.8 mmol) was dissolved in 4 M HCl-dioxane (5 ml). Thesolution was stirred at r.t. until all starting material was consumed.The solvent was evaporated under reduced pressure and the white solidwas triturated with diethyl ether to afford pure product of the titlecompound (0.84 g, <99%). MS (M+H) 433, HPLC retention time 2.07 min.

Examples 2 to 15

Examples 2-15 in Table 1 have been synthesized utilizing the proceduresdescribed in Example 1, utilizing the appropriate starting materials.TABLE 1

Compound HPLC Purity number R (%) HPLC Retention (min) Mass M + H 2

100 2.53 422 3

90 1.93 399 4

90 1.92 388 5

91 1.60 372 6

90 1.29 354 7

99 1.60 379 8

94 2.46 422 9

96 1.80 432 10

94 1.73 388 11

89 1.73 399 12

91 2.37 456 13

100 2.40 435 14

100 2.12 435 15

88 1.97 384

Example 162-Amino-2-methyl-N-[3-phenyl-1-(6-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-propyl]-propionamide

To a THF (100 ml) solution of2-tert-Butoxycarbonylamino-4-phenyl-butyric acid (2.0 g, 7.1 mmol) wasadded TEA (0.98 ml, 7.1 mmol), followed by the addition of iso-butylchloroformate (0.98 g, 7.1 mmol) dropwise. A White suspension wasformed. This suspension was stirred at r.t. for 10 min and then(5-Trifluoromethyl-pyridin-2-yl)-hydrazine (1.3 g, 7.1 mmol) was addedin three portions. The resulting suspension was stirred at r.t. for 1 hand then the solvent was removed under reduced pressure until a thickslurry was formed. Water (200 ml) was added and the suspension wasstirred to ensure the solid was finely dispersed. The off-white solidwas filtered and washed with NaOH (1N, 100 ml), water (100 ml) and HCl(1N, 100 ml) and then water (200 ml) dried to give 16A (1.9 g, 100%).

To a THF (100 ml) solution of 16A (1.9 g, 4.3 mmol) was addedtriphenylphosphine (1.3 g, 5.2 mmol), and trimethylsilyl azide (0.6 g,5.2 mmol). To this solution was added diethyl diazacarboxylate (DEAD,1.8 g, 10.8 mmol) in rapid drops. The solution became hot. After theaddition was complete, the solution was allowed to stir at r.t. untilall starting material was consumed (<2 h). The solvent was removed underreduced pressure to give 16B

16B was suspended in HCl-dioxane (160 ml, 4M HCl in dioxane). Thesuspension was stirred at r.t. until all of the starting material wasconsumed. The suspension was concentrated to a thick slurry and thendiluted with THF (100 ml). The solid was collected by filtration andrinsed with excess CH₂Cl₂, diethyl ether, and dried to give 16C

To a THF (100 ml) solution of2-tert-butoxycarbonylamino-2-methyl-propionic acid (27.5 mg, 0.135 mmol)was added EDAC (29.2 mg, 0.15 mmol) and HOBT (20 mg, 0.15 mmol), DMAP(1.5 mg, 0.01 mmol), and pyridine. This solution was stirred at r.t. for10 min before the addition of 16C (52 mg, 0.123 mmol). The reaction wascompleted in <1 h. The solvent was then removed under reduced pressureand the residue was dissolved in EtOAc (200 ml). The organic solutionwas washed with water (200 ml), NaOH (0.5 N, 200 ml), HCl (0.5 N, 200ml), and water (200 ml). The organic layer was dried over Na₂SO₄ andconcentrated to give a white solid 16D

16D was dissolved in 4 M HCl-dioxane (5 ml). The solution was stirred atr.t. until all starting material was consumed. The solvent wasevaporated under reduced pressure and the white solid was trituratedwith diethyl ether to afford pure product (29 mg, 94%). MS (M+H) 406,HPLC retention time 2.3 min.

The following compounds have been prepared utilizing the proceduresdescribed in Example 16, which started with the corresponding acids(step A), hydrazines (step A) and amines (Step D) as depicted in Table2. TABLE 2 Compound HPLC Purity HPLC Retention number (%) (min) Mass 17

98 2.28 432 18

91 2.28 432 19

95 2.47 441 20

98 2.26, 2.42 432 21

98 2.35 432 22

94 2.31 418 23

93 2.47 446 24

95 2.39 420 25

88 2.34 420

Example 266-Amino-N-[2-phenyl-1-(6-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-ethyl]-nicotinamide

To a THF (100 ml) solution of2-tert-Butoxycarbonylamino-3-phenyl-propionic acid (2.0 g, 7.1 mmol) wasadded TEA (0.98 ml, 7.1 mmol), followed by the addition of iso-butylchloroformate (0.98 g, 7.1 mmol) dropwise. A White suspension wasformed. This suspension was stirred at r.t. for 10 min and then(5-Trifluoromethyl-pyridin-2-yl)-hydrazine (1.3 g, 7.1 mmol) was addedin three portions. The resulting suspension was stirred at r.t. for 1 hand then the solvent was removed under reduced pressure until a thickslurry was formed. Water (200 ml) was added and the suspension wasstirred to ensure the solid was finely dispersed. The off-white solidwas filtered and washed with NaOH (1N, 100 ml), water (100 ml) and HCl(1N, 100 ml) and then water (200 ml) dried to give 26A (1.9, 100%).

Example 26 was prepared utilizing the procedures described in Example16, substituting with 26A for 16A, 26B for 16B, 26C for 16C, 26D for16D. Example 26 was obtained as a white foam. MS (M+H) 427, HPLCretention time 2.23 min.

The following compounds have been prepared utilizing the proceduresdescribed in Example 26 as depicted in Table 3. TABLE 3 Compound HPLCPurity number (%) HPLC Retention (min) Mass 27

95 2.03 418 28

93 2.02 418 29

98 2.00 392 30

98 2.02, 2.16 418 31

80 2.08 418 32

88 2.06 404 33

90 2.15 432 34

88 2.14 406 35

76 2.07 406

Example 366-N-[2-benzyloxy-1-(6-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-ethyl]-nicotinamide

To a THF (100 ml) solution of3-Benzyloxy-2-tert-butoxycarbonylamino-acid propionic acid (2.0 g, 7.11mmol) was added TEA (0.98 ml, 7.1 mmol), followed by the addition ofiso-butyl chloroformate (0.98 g, 7.1 mmol) dropwise. A White suspensionwas formed. This suspension was stirred at r.t. for 10 min and then(5-Trifluoromethyl-pyridin-2-yl)-hydrazine (1.3 g, 7.1 mmol) was addedin three portions. The resulting suspension was stirred at r.t. for 1 hand then the solvent was removed under reduced pressure until a thickslurry was formed. Water (200 ml) was added and the suspension wasstirred to ensure the solid was finely dispersed. The off-white solidwas filtered and washed with NaOH (1N, 100 ml), water (100 ml) and HCl(1N, 100 ml) and then water (200 ml) dried to give 36A (1.9, 100%).

Example 36 was prepared utilizing the procedures described in Example16, substituting with 36A for 16A, 36B for 16B, 36C for 16C, 36D for16D. Example 36 was obtained as a white foam. MS (M+H) 456, HPLCretention time 2.4 in.

The following compounds have been prepared utilizing the proceduresdescribed in Example 36 as depicted in Table 4. TABLE 4 HPLC CompoundRetention number HPLC Purity (%) (min) Mass 37

98 2.38 447 38

100 2.29 447 39

97 2.31 447 40

95 2.08 445 41

95 2.22 473 42

97 2.11 447 43

90 2.09 447 44

96 2.09 459

Example 452-Amino-N-{2-benzyloxy-1-[6-(2-fluoro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]-ethyl}-2-methyl-propionamide

Compound 1D (300 mg, 0.56 mmol), 2-fluorophenylboronic acid (120 mg,0.86 mmol), Pd(OAc)₂ (5 mg, 0.022 mmol), triphenyl phosphine (100 mg,0.38 mmol), and Et₃N (0.24 ml, 1.72 mmol) were dissolved in DMF (2 ml).This solution was heated at 110° C. for 12 h. The resulted mixture wasdiluted with water (10 ml) and was extracted with EtOAc. The combinedorganic portion was washed with NH₄OH (10%) and brine and dried overanhydrous MgSO₄. The solvent was evaporated under reduced pressure toafford a stick liquid. The products were not purified and used directlyfor the next step.

Example 45

45A was dissolved in 4 M HCl-dioxane (2 ml). The solution was stirred atr.t. until all starting material was consumed. The solvent wasevaporated under reduced pressure. The product was purified bypreparative HPLC to give the title compound (129 mg, 50%). MS (M+H) 447,HPLC retention time 2.47 min.

The following compounds has been prepared by utilizing the intermediatesgenerated in Example 1 with chemical sequences described in Example 45,utilizing the appropriate starting materials as depicted in Table 5.TABLE 5

HPLC Compound HPLC Purity Retention number Ar (%) (min) Mass 46

100 2.45 430 47

100 2.47 460 48

98 2.63 464 49

99 2.66 497 50

100 2.56 477

Example 512-Amino-N-[2-benzyloxy-1-(6-methanesulfonylamino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-ethyl]-2-methyl-propionamide

Compound 51A was obtained using the same procedures described for thesynthesis of 1D with 5-nitro-2-hydrazinopyridine in place of5-bromo-2-hydrazinopyridine.

Compound 51A (1.3 g, 2.6 mmol) was dissolved in EtOH (60 ml). Pd/C (35mg, 10% Pd by weight) was added under N₂. This mixture was thensubjected to hydrogenation at 50 Psi for 3 h to afford 51B. Solvent wasremoved under reduced pressure and the product was pure enough (>90%)and was used directly for the next reactions.

Compound 51B (200 mg, 0.43 mmol) was dissolved in CH₂Cl₂ (5 ml) andpyridine (0.14 ml, 2.1 mmol) was added. To this solution was added thecorresponding methyl sulfonyl chloride (0.05 ml, 0.65 mmol). Reactionswere completed in 1.5 h. The reactions were then diluted with CH₂Cl₂ (25ml) and washed with HCl (1N, 20 ml), aqueous saturated NaHCO₃ (20 ml),and water (20 ml). Purification by flash chromatography on silica gel(5% CH₃OH/as elutant) gave 51C (90 mg, 40%).

Example 51

Compound 51C was dissolved in HCl (4 ml, 4M in dioxane) and was stirredat r.t. until the reaction was completed. The solvent was removed underreduced pressure. The products were purified by preparative HPLC to givethe title compound as a foam (60 mg, 82%). MS (M+H) 447, HPLC retentiontime 1.73 min.

The following compounds in Table 6 have been synthesized utilizing theprocedures described in Example 51, utilizing the appropriate startingmaterials. TABLE 6

HPLC Compound HPLC Purity Retention number R (%) (min) Mass 52

90 2.32 509 53

97 2.02 475 54

97 2.23 515

Example 55N-[1-(6-Acetylamino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-benzyloxy-ethyl]-2-amino-2-methyl-propionamide

Compound 51B (130 mg, 0.28 mmol) was dissolved in CH₂Cl₂ (2 ml) and Et₃N(0.2 ml, 1.4 mmol) was added. To this solution was added acetyl chloride(0.026 ml, 0.36 mmol). After stirring overnight at r.t, the reaction wasthen diluted with CH₂Cl₂ (25 ml) and washed with HCl (1N, 20 ml), NaHCO₃(sat. 20 ml), and water (20 ml). The crude product were purified withflash chromatography (5% CH₃OH/CH₂Cl₂) to give 55A (80 mg, 56%).

Example 55

Compound 55A was dissolved in HCl (4 ml, 4M in dioxane) and was stirredat r.t. until the reaction was completed. The solvent was removed underreduced pressure. The products were purified by preparative HPLC to givethe title compound as a foam. MS (M+H) 411, HPLC retention time 1.86min.

The following compounds in Table 7 have been synthesized utilizing theprocedures described in Example 55, utilizing the appropriate startingmaterials. TABLE 7

HPLC Compound HPLC Purity Retention number R (%) (min) Mass 56

88 2.24 439

Example 572-Amino-N-[2-benzyloxy-1-(6-chloro-5-dimethylamino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-ethyl]-2-methyl-propionamide

Compound 57A was obtained using the same procedures described for thesynthesis of 1D with the corresponding 2-hydrazinopyridine.

Compound 57A (250 mg, 0.48 mmol) in Dimethylamine (3 ml) was heated at100° C. for 1.5 h. The reaction was diluted with water (10 ml) andextracted with EtOAc. The combined organic portions were dried overNa₂SO₄ and the solvent was evaporated under reduced pressure. The crudeproduct was purified with flash chromatography (2% CH₃OH/CH₂Cl₂) to give57B (140 mg, 55%).

Example 57

57A (140 mg, 0.26 mmol) was dissolved in HCl (5 ml, 4 M HCl in dioxane)and stirred at r.t. until all the starting materials was consumed.Purification by preparative HPLC gave the title compound (51 mg). MS(M+H) 431, HPLC retention time 2.35 min.

The following compounds in Table 8 have been synthesized utilizing theprocedures described in Example 57, utilizing the appropriate startingmaterials. TABLE 8

Compound HPLC Purity HPLC Retention number Substituted Triazolopyridine(R) (%) (min) Mass 58

96 1.51 397 59

60

61

98 2.51 431 62

97 1.34 475

Example 632-Amino-N-{2-benzyloxy-1-[6-chloro-5-(2-methoxy-ethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]-ethyl}-2-methyl-propionamide

Compound 57A (250 mg, 0.48 mmol) in 2-Methoxy-ethanol (1 ml) and Cesiumcarbonate (155 mg, 0.48 mmol) was heated at 100° C. for 1.5 h. Thereaction was diluted with water (10 ml) and extracted with EtOAc. Thecombined organic portions were dried over Na₂SO₄ and the solvent wasevaporated under reduced pressure to give 63A.

Example 63

63A was dissolved in HCl (5 ml 4 M HCl in dioxane) and stirred at r.t.until all the starting materials was consumed. Purification bypreparative HPLC gave the title compound (18.6 mg). MS (M+H) 462, HPLCretention time 2.23 min.

The following compounds in Table 9 have been synthesized utilizing theprocedures described in Example 63, utilizing the appropriate startingmaterials. TABLE 9

Compound number R HPLC Purity (%) HPLC Retention (min) Mass 64

90 1.97 420 65

66

67

68

Example 693-[1-(2-Amino-2-methyl-propionylamino)-2-benzyloxy-ethyl]-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid methylamide

To 1D (0.7 g, 1.32 mmol) in DMF (10 ml) and MeOH (5 ml) was added1,3-Bis(diphenylphosphino)-propane (217 mg, 0.53 mmol), DBU (240 mg,1.58 mmol) and palladium acetate (148 mg, 0.66 mmol). The mixture wasdegassed and the flushed with carbon monoxide and kept at 20 psi. Thereaction was heated at 85° C. overnight. The catalyst was filtered andthe solution concentrated. The residue was taken in EtOAc, washed withwater, brine, dried and concentrated. The crude product was purifiedwith flash chromatography to give 69A as a white foam.

To 69A (2.3 g, 4.5 mmol) in THF (20 ml) was added lithium hydroxide (40ml of 2N solution). The mixture was stirred for 3 h at r.t. 1NHCl wasadded to adjust the pH to 2. The solution was extracted with CH₂Cl₂,washed, dried and concentrated to give 69B.

To a CH₂Cl₂ (2 ml) solution of 69B (150 mg, 0.3 mmol) was added EDAC (86mg, 0.45 mmol) and HOBT (60 mg, 0.45 mmol) and (i-Pr)₂NEt (58 mg, 0.45mmol) and then 2M solution of methylamine in THF (0.225 ml, 0.45 mmol)The reaction was stirred overnight and then extracted with EtOAc Theorganic solution was washed with water, brine, dried and concentrated togive a white solid 69C.

Example 69

69C was dissolved in HCl (5 ml 4 M HCl in dioxane) and stirred at r.t.until all the starting materials was consumed. Purification bypreparative HPLC gave the title compound as an oil. MS (M+H) 410, HPLCretention time 2.4 min.

The following compounds in Table 10 have been synthesized utilizing theprocedures described in Example 69, utilizing the appropriate startingmaterials. TABLE 10

HPLC Compound Retention number R HPLC Purity (%) (min) Mass 70

93 2.56 468 71

90 2.13 487 72

90 2.00 505 73

93 1.39 396 74

95 2.39 432

Example 75 Methyl-carbamic acid3-[1-(2-amino-2-methyl-propionylamino)-2-benzyloxy-ethyl]-[1,2,4]triazolo[4,3-a]pyridin-6-ylmethylester

To a stirred solution of 59A (50 mg, 0.098 mmol) in CH₂Cl₂ at −78° C.was added 1.5M solution of DIBAL in toluene (0.4 ml, 0.58 mmol) andstirred at r.t. overnight. The solution was cooled to 0° C. and then a1M solution of sodium potassium tartarate was added slowly. Stirred for1.5 h at r.t. The precipitate formed is filtered off through a pad ofcelite. And then extracted with CH₂Cl₂, washed, dried and concentratedto give 75A.

To 75A (180 mg, 0.2 mmol) in CH₂Cl₂ (2 ml) 0° C. was added TEA (60 mg,0.6 mmol) and methyl isocyanate (24 mg, 0.4 mmol). Reaction was warmedto r.t. and stirred overnight. The solution was concentrated to give 75B

Example 75

75B was dissolved in HCl (5 ml 4 M HCl in dioxane) and stirred at r.t.until all the starting materials was consumed. Purification bypreparative HPLC gave the title compound as oil. MS (M+H) 441, HPLCretention time 2.48 min.

Example 763-[1-(2-Amino-2-methyl-propionylamino)-2-benzyloxy-ethyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylicacid ethyl ester

To a cooled solution of potassium hydroxide (100 ml, 40% in water) inether (500 ml) at 0° C. was added 1-methyl-3-nitro-1-nitoroguanidine (15g, 0.102 mol) slowly over 15 min. The upper organic phase was pouredinto a flask containing 30 g potassium hydroxide. After 5 min. the ethersolution was slowly added to3Benzyloxy-2-tert-butoxycarbonylamino-propionic acid (20.5 g, 0.069 mol)in THF/CH₂Cl₂ (200 ml). After stirring for 5 min the solution wasconcentrated to give 76A.

To a solution of 76A (22.8 mg, 74.8 mmol) in 250 ml MeOH was addedhydrazine (4.8 g, 149.8 mmol) and the mixture refluxed for 2 days. Thesolution was concentrated to give crude 76B.

To a solution of 2-Oxo-piperidine-3-carboxylic acid ethyl ester (0.86 g,5 mmol) in CH₂Cl₂ (10 ml) was added trimethyloxonium tetrafluoroborate(0.74 g, 5 mmol) and stirred overnight followed by addition of 76B (1.5g, 5 mmol). The mixture was stirred for 24 h. The solution was dilutedwith CH₂Cl₂, washed with water, brine, dried and concentrated to give76C as a white foam (2.5 g, <99%).

The solution of 76C (1.3 g, 2.8 mmol) in MeOH (27 ml) was refluxed for 4days. The mixture was concentrated to give 76D.

To 76D (1.2 g, 2.8 mmol) in CH₂Cl₂ was added HCl (5 ml 4 M HCl indioxane) and stirred at r.t. until all the starting materials wasconsumed. The solution was concentrated. To a CH₂Cl₂ (15 ml) solution ofthe residue was added EDAC (0.8 g, 0.4.16 mmol) and HOBT (0.56 g, 4.16mmol) and (i-Pr)₂NEt (7.15 g, 55.4 mmol) and2-tert-butoxycarbonylamino-2-methyl-propionic acid (0.68 g, 3.32 mmol).The reaction was stirred overnight and then extracted with EtOAc. Theorganic solution was washed with water, brine, dried and concentrated.Purification by flash chromatography on silica gel (5% CH₃OH/CH₂Cl₂ aselutant) gave 76E.

Example 76

76E (50 mg, 0.1 mmol) in CH₂Cl₂ (5 ml) was treated with HCl (2 ml 4 MHCl in dioxane) and stirred at r.t. until all the starting materials wasconsumed. Purification by preparative HPLC gave the title compound as asalt (22 mg, 55%). MS (M+H) 430, HPLC retention time 2.63 min.

Example 772-Amino-N-[2-benzyloxy-1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-ethyl]-2-methyl-propionamide

To a solution of 76E (0.32 g, 0.6 mmol) in THF (1 ml) was added H₂O (4ml), MeOH (0.5 ml) and Lithium hydroxide (6 ml of 4N solution). Themixture was stirred at r.t. for 1.5 h. The pH of the solution wasadjusted to 2 with the slow addition of 1N HCl, followed by extractionwith CH₂Cl₂ washed with water, brine, dried and concentrated to give 77A(270 mg, 89%)

Example 77

To 77A (135 mg, 0.27 mmol) in ether (2.5 ml) was added methylamine (0.27ml, 0.54 mmol, 2M in THF), HOBT (73 mg, 0.54 mmol) and EDAC (103 mg,0.54 mmol). After stirring for 24 h, the solution was extracted withCH₂Cl₂, washed with water, brine, dried and concentrated. The residue inCH₂Cl₂ (2 ml) was treated with HCl (1 ml 4 M HCl in dioxane) and stirredat r.t. until all the starting materials was consumed. Purification bypreparative HPLC gave the title compound as a foam (61 mg, 65%). MS(M+H) 358, HPLC retention time 1.86 min.

Example 783-[1-(2-Amino-2-methyl-propionylamino)-2-benzyloxy-ethyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylicacid ethyl ester

To a solution of ethyl isonipecotate (20.4 g, 0.13 mmol) in CH₂Cl₂ (120ml) was added di-tert-butyl dicarbonate (31.1 g, 0.13 mol). After 5 h ofstirring at r.t, the reaction was quenched with water and extracted withCH₂Cl₂, washed with water, brine, dried and concentrated. Purificationby flash chromatography on silica gel (1:6 EtOAc/hexane as elutant) gave78A.

To a solution of 78A (10.38 g, 40.4 mmol) in water (120 ml) andacetonitrile (25 ml) at r.t. was added sodium periodate (25.9 g, 121.1mmol) and ruthinium oxide (0.5 g, 3.63 mmol). After stirring for 6 h themixture was filtered. The residue was washed with CH₂Cl₂ and the aqueouslayer was extracted with CH₂Cl₂, dried and concentrated. The residue inCH₂Cl₂ (100 ml) was treated with HCl (14 ml 4 M HCl in dioxane) andstirred at r.t. until all the starting materials was consumed.Purification by flash chromatography on silica gel (5% CH₃OH/CH₂Cl₂ aselutant) gave 78B.

78C was prepared using the method described in 76C substituting2-Oxo-piperidine-3-carboxylic acid ethyl ester with 78B (1.2 g, 7.1mmol) and 76B (2.9 g, 7.1 mmol). 78C was obtained as a colorless oil(3.4 g, <99%).

Example 78 was prepared by using the same methods as described toprepare 76D substituting 76C with 78C to provide the title compound as afoam (17 mg). MS (M+H) 430, HPLC retention time 2.56 min.

Preparative HPLC separation of Example 78 gave the two diastereomers asExample 78a MS (M+H) 430, HPLC retention time 2.55 min and Example 78bMS (M+H) 430, HPLC retention time 1.89 min.

Example 793-[1-(2-Amino-2-methyl-propionylamino)-2-benzyloxy-ethyl]-7-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylicacid methyl ester

To a cooled solution of potassium hydroxide (15 ml, 40% in water) inether (100 ml) at 0° C. was added 1-methyl-3-nitro-1-nitoroguanidine (5g, 34 mmol) slowly over 15 min. The upper organic phase was poured intoa flask containing 30 g potassium hydroxide. After 5 min the ethersolution was slowly added to 4-formyl-4-phenyl-piperidine-1-carboxylicacid tert-butyl ester (4.15 g, 13.6 mmol) in THF (20 ml). After stirringfor 5 min the solution was concentrated to give 79A (4.4 g, <99%).

79B was prepared using the method described in 78B substituting 78A with79A (4 g, 12.5 mmol) and. 79B was obtained as a colorless oil (3.1 g,75%).

79B (3.1 g, 9.3 mmol) in CH₂Cl₂/MeOH (6 ml/6 ml) was treated with HCl (5ml 4 M HCl in dioxane) and stirred at r.t. until all the startingmaterials was consumed. Purification by flash chromatography on silicagel (5% CH₃OH/CH₂Cl₂ as elutant) gave 79C.

79D was prepared using the method described in 76C substituting2-Oxo-piperidine-3-carboxylic acid ethyl ester with 79C (830 mg, 35.6mmol) and 76B (2.9 g, 7.1 mmol). 79D was obtained as a colorless oil(2.2 g, <99%).

Example 79 was prepared by using the same methods for 76D, 76E andexample 76 substituting 76C with 79D, 76D with 79E 76E with 79F toprovide the title compound as a foam (8.5 mg). MS (M+H) 492, HPLCretention time 2.91 min.

Example 80 and Example 81

Example 79 was subjected to preparative HPLC to separate thediastereomers to give 24 mg of Example 80 (MS (M+H) 492, HPLC retentiontime 2.89 min) & 34 mg of Example 81 (MS (M+H) 492, HPLC retention time3.01 min)

Example 823-[1-(2-Amino-2-methyl-propionylamino)-2-benzyloxy-ethyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylicacid ethylamide

82A was prepared using the method described in 77A substituting 76E with78D (200 mg, 0.38 mmol) and. 82A was obtained as a colorless oil (168mg, 89%).

Example 82

To a solution of 82A (89 mg, 0.18 mmol) in CH₂Cl₂ (2 ml) at −40° C. wasadded N-methyl morpholine and isobutyl chloroformate (24.3 mg, 0.18mmol). The mixture was stirred for 1 h at −40° C. Then 2M solution ofethylamine in THF (90 μl, 0.18 mmol) was added. The reaction was slowlywarmed up to r.t. and concentrated. The residue was redissolved inCH₂Cl₂ (2 ml) was treated with HCl (1 ml 4 M HCl in dioxane) and stirredat r.t. until all the starting materials was consumed. Purification bypreparative HPLC gave the title compound as a salt (14 mg, 20%). MS(M+H) 429, HPLC retention time 1.89 min.

Compounds 83 and 83a were synthesized utilizing the procedures describedin Example 82, utilizing the appropriate starting materials. 83  

90 2.42 491 83a Other diastereomer

95 2.73 491

Example 84 2-Amino-N-[1-(6-chloro-benzo[d]isoxazol-3-yl)₄-phenyl-butyl]-2-methyl-propionamide

To 60 ml of EtOH was added Na metal (2.3 g, 100 mmol) slowly & stirredfor 30 min. until all the Na metal had dissolved. 2-Acetyl amino-malonicacid diethyl ester (21.7 g, 100 mmol) was then added. After stirring for1 h at r.t, (3-bromo-propyl)-benzene (15.2 ml, 100 mmol) was added &then heated at 75° C. overnight. The mixture was quenched with waterextracted with EtOAc, dried over Na₂SO₄, filtered & concentrated. Theresidue was triturated with hexane to give a white solid 84A (18.7 g,81%)

To a stirred solution of A (4.3 g, 18.7 mmol) in 1N NaOH (56 ml) and THF(50 ml), Di-tert-butyl dicarbonate (4.9 g, 22.5 mmol) was added at RT.After 3 h of stirring benzenethiol (3.1 g, 28.1 mmol), EDAC (7.1 g, 37mmol) and HOBT (5.1 g, 37 mmol) were added and the reaction mixture wasstirred at r.t. overnight. The mixture was extracted with EtOAc washedwith water, dried over Na₂SO₄, filtered & concentrated. Purification byflash chromatography on silica gel (1:9 EtOAc/hexane as elutant) gave awhite solid 84B (3.8 g, 53%).

To 84B (1.1 g, 3.8 mmol) in THF (10 ml) under nitrogen was addeddichlorobis (triphenylphosphine) Palladium (II) (200 mg, 0.28 mmol) at0° C. followed by 3-chloro-4-flouro phenylzinc iodide (17 ml, 8.5 mmol)0.5M in THF via syringe. After stirring the mixture at r.t. for 3 h itwas quenched with water extracted with EtOAc, dried over Na₂SO₄,filtered and concentrated. Purification by flash chromatography onsilica gel (1:9 EtOAc/hexane as elutant) gave a white solid 84C (710 mg,45%)

To a stirred solution of 84C (700 mg, 1.7 mmol) in pyridine (5 ml) wasadded Hydroxylamine hydrochloride (240 mg, 3.4 mmol) & heated in asealed tube for 2 h. The mixture was concentrated, the residue dissolvedin DMF (5 ml) and potassium hydroxide (450 mg, 6.8 mmol) added. Themixture was heated at 85° C. overnight, quenched with water extractedwith EtOAc, dried over Na₂SO₄, filtered and concentrated. Purificationby flash chromatography on silica gel (1:9 EtOAc/hexane as elutant) gavea white solid 84D (390 mg, 57%)

To a stirred solution of 84D (390 mg, 0.97 mmol) was added 5 ml of 20%TFA/CH₂Cl₂ and stirred at r.t. for 2 h. The mixture was concentrated,the residue dissolved in 1N NaOH, water brine, dried and concentrated.The residue was taken in 5 ml CH₂Cl₂ & Boc-2-Aminoisobutyric acid (390mg, 1.9 mmol), 1-Hydroxybenzotriazole hydrate (270 mg, 2 mmol), EDAC(380 mg, 2 mmol) were added. The mixture was stirred at r.t. overnight,extracted with EtOAc washed with water, dried over Na₂SO₄, filtered &concentrated. Purification by flash chromatography on silica gel (1:9EtOAc/hexane as elutant) gave a white solid 84E (360 mg, 76%).

Example 84

A solution of 84E (13 mg, 0.03 mmol) in 1 ml of 20% TFA/CH₂Cl₂ wasstirred for 1 h and then concentrated. The residue was purified bypreparative HPLC to give the title compound as a white solid (34.5 mg,53%). MS (M+H) 386, HPLC retention time 3.32 min.

Example 852-Amino-N-[1-(5-chloro-benzo[d]isoxazol-3-yl)₄-phenyl-butyl]-2-methyl-propionamide

To a stirred solution of 2,5-Dichloro-benzoic acid (3.5 g, 18.3 mmol) inCH₂Cl₂ (5 ml) was added Oxalyl chloride (18.3 ml, 2M in CH₂Cl₂) followedby several drops of DMF. The mixture was stirred at r.t. for 2 h andconcentrated. The residue was dissolved in CH₂Cl₂ (20 ml) & TEA (7.6 ml,55 mmol) was added followed by N,O-Dimethylhydroxyamine hydrochloride(3.6 g, 36.6 mmol). The mixture was stirred at r.t. overnight &extracted with EtOAc washed, dried, filtered & concentrated.Purification by flash chromatography on silica gel (EtOAc/hexane aselutant) gave a pale brown solid 85A (3 g, 67%).

To But-3-ynyl-benzene (1.5 g, 11.5 mmol) in THF (15 ml) at 0° C. wasadded nbuLi (5.3 ml, 2.5M in hexane) via syringe. After stirring for 30min. 85A (2.4 g, 10.3 mmol) in 5 ml THF was added followed by additional1 h of stirring at 0° C. The mixture was quenched with water, extractedwith EtOAc, dried over Na₂SO₄, filtered & concentrated. Purification byflash chromatography on silica gel (1:9 EtOAc/hexane as elutant) gave ayellow liquid 85B (1.3 g, 42%)

To C (1.3 g, 4.3 mmol) in MeOH (15 ml) and EtOAc (5 ml) was added Pd—Ccatalyst (260 mg, 5% by weight of palladium) and stirred at r.t. with ahydrogen balloon for 6 h. The catalyst was filtered and concentrated.Purification by flash chromatography on silica gel (5:95 EtOAc/hexane aselutant) gave a yellow liquid 85C (1.1 g, 85%).

To a stirred solution of 85C (900 mg, 2.9 mmol) in dioxane (5 ml) wasadded bromine (470 mg, 2.9 mmol) in dioxane (5 ml) slowly at r.t. viasyringe & then stirred overnight. The mixture was quenched with waterextracted with EtOAc, dried over Na₂SO₄, filtered & concentrated & theresidue passed through a silica pad to give a pale yellow oil as theintermediate. The intermediate was dissolved in acetone (10 ml) andsodium azide (200 mg, 3.1 mmol) in 2 ml water was added. The mixture wasstirred at r.t. for 30 min and concentrated, extracted with EtOAc, driedover Na₂SO₄, filtered & concentrated. Purification by flashchromatography on silica gel (1:9 EtOAc/hexane as elutant) gave 85D (710mg, 70%).

To 85D (710 mg, 2 mmol) in MeOH (10 ml) was added di-tert-butyldicarbonate (1.3 g, 6 mmol) and Pd—C catalyst (70 mg, 5% by weight ofpalladium) and stirred at r.t. with a hydrogen balloon overnight. Thecatalyst was filtered & concentrated. Purification by flashchromatography on silica gel (1:9 EtOAc/hexane as elutant) gave a whitesolid 85E (250 mg, 89%).

85F was prepared using the method described in 84D substituting 84C with85E (650 mg, 1.5 mmol) and hydroxylamine hydrochloride (210 mg, 3 mmol)& potassium hydroxide (400 mg, 6 mmol). 85F was obtained as a colorlessoil (490 mg, 81%).

85G was prepared using the method described in 84E substituting 84D with85F (490 mg, 1.2 mmol) and Boc-2-Aminoisobutyric acid (490 mg, 2.4mmol). 85G was obtained as a colorless oil (540 mg, 91%).

85G was subjected to chiral separation using chiral prep HPLC (ChiralpakAD 5 cm×50 cm 2 μm) & 20% IPA/hexane as elutant) to give 265 mg of 85H(rt=6.54 min)) & 265 mg of 85I (rt=12.85 min).

Example 85

85I (265 mg, 0.55 mmol) was treated with 3 ml of 20% TFA/CH₂Cl₂according to the method for Example 84 to give the title compound as awhite solid (245 mg) with 99% purity. MS (M+H) 387, HPLC retention time3.34 min.

Example 862-Amino-N-[1-(5-chloro-benzo[d]isoxazol-3-yl)₄-phenyl-butyl]-2-methyl-propionamide

86H (10 mg, 0.02 mmol) was treated with 20% TFA/CH₂Cl₂ (0.7 ml)according to the method for Example 84 to give the title compound as awhite solid (7.4 mg) with 97% purity. MS (M+H) 386, HPLC retention time3.37 min.

Example 872-Amino-N-[1-(6-methanesulfonyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-phenyl-propyl]-2-methyl-propionamide

To 1C (200 mg, 0.447 mmol) in THF (3 ml) was added isopropyl magnesiumchloride (1.34 ml, 2.68 mmol, 2M solution) at r.t. After 1 h ofstirring, dimethyldisuiphide (94.2 mg) was added and stirred overnight.Diluted with water and extracted with CH₂Cl₂, dried and concentrated.Purification by flash chromatography on silica gel (1:1 EtOAc/hexane aselutant) gave a white solid 87A.

To 87A (15 mg, 0.43 mmol) in CHF₂Cl₂ (1 ml) was added m-chloroperbenzoic acid (21 mg, 0.07) and stirred for 2 h. The mixture wasconcentrated and redissolved in CH₂Cl₂ washed with 1N NaOH, brine, driedand concentrated. The residue in MeOH (11 ml) was treated with 4NHCl (1ml) for 3 h at r.t. and then concentrated. The residue was taken in 1.5ml CH₂Cl₂ & Boc-2-Aminoisobutyric acid (390 mg, 1.9 mmol), 1-HOAT (10mg, 0.07 mmol), EDAC (14 mg, 0.072 mmol) and TEA (20 μl, 0.144 mmol)were added. The mixture was stirred at r.t. overnight, extracted withEtOAc washed with water, dried over Na₂SO₄, filtered & concentrated togive 87B

Example 87

A solution of 87B in MeOH (1 ml) was treated with 4N HCl (1 ml) andstirred for 1 h and then concentrated. The residue was purified bypreparative HPLC to give the title compound as a white solid (15 mg). MS(M+H) 432, HPLC retention time 2.4 min.

Example 88 Methyl-carbamic acid3-[1-(2-amino-2-methyl-propionylamino)-2-benzyloxy-ethyl]-7-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-7-ylmethylester

To a solution of 79E (350 mg, 0.6 mmol) in CH₂Cl₂ (6 ml) was addedlithium borohydride (1.2 ml, 2.4 mmol, 2M solution) at 0° C. The mixturewas warmed to r.t. and stirred overnight. The reaction was quenched withpH 3 buffer, stirred for 30 min and extracted with CH₂Cl₂, washed withbrine, dried, filtered and concentrated to give crude product 88A (336mg, <99%)

Example 88

To a solution of 88A in CH₂Cl₂ (3 ml) at 0° C. was added TEA (127 μl,0.91 mmol) and methylisocyanate (35 mg, 0.61 mmol). The mixture waswarmed to r.t. and stirred overnight. The residue in CH₂Cl₂ (3 ml) wastreated with HCl (1.5 ml 4 M HCl in dioxane) and stirred at r.t. untilall the starting materials was consumed. Purification and separation byPreparative HPLC gave the two diastereomers as Example 88a MS (M+H) 521,HPLC retention time 2.55 min and Example 88b MS (M+H) 521, HPLCretention time 2.92 min.

Example 892-Amino-N-[2-benzyloxy-1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-2-methyl-propionamide

To a slurry of 3-Benzyloxy-2-butoxycarbonylamino-propionic acid (740 mg,2.5 mmol) in CH₂Cl₂ (10 mL) was added EDAC (475 mg, 2.5 mmol) at r.t.After stirring for 1 h (6-chloropyridazin-3-yl)hydrazine (362 mg, 2.5mmol) was added. After 2 h, the reaction was quenched with saturatedaqueous NaHCO₃. The mixture was extracted with EtOAc, dried, filteredand concentrated. Purification by flash chromatography on silica gel(1:2 EtOAc/hexane as elutant) gave 89A (730 mg, 69%) as a yellow foam.

To a solution of 89A (210 mg, 0.5 mmol) in acetonitrile (5 mL) at 0° C.was added 1,2-dibromo-1,1,2,2-tetrachloroethane (179 mg, 0.55 mmol)followed by triethylamine (0.31 mL, 2.2 mmol) and triphenylphosphine(289 mg, 1.1 mmol). After stirring for 1 h, the mixture was warmed tor.t. and stirred for 2 h. The solution was concentrated and the residuewas redissolved in EtOAc, washed with 1:1 brine/10% citric acid, brine,dried, filtered and concentrated. Purification by preparative HPLC gave89B as an off-white solid (125 mg, 62%).

To MeOH (3.5 ml) at 0° C. was added acetyl chloride (0.8 mL) over 3 min.After stirring the solution for 1 h, the solution was added to 89B (125mg, 0.31 mmol) in CH₂Cl₂ (0.3 ml) at r.t. The mixture was stirred atr.t. for 2 h and then concentrated twice from CH₂Cl₂. The residue wasredissolved in CH₂Cl₂ (1 mL) and added to a slurry ofBoc-2-aminoisobutyric acid (94.4 mg, 0.46 mmol), HOAT (63.6 mg, 0.46mmol) and N-methyl morpholine (0.051 ml, 0.5 mmol) in CH₂Cl₂ (2 ml). Thesolution was stirred for 15 h, diluted with EtOAc, washed with saturatedaqueous NaHCO₃, dried, filtered and concentrated. Purification by flashchromatography on silica gel (1:99 MeOH/EtOAc as elutant) gave 89C as acolorless foam (69 mg, 46%).

Example 89

To MeOH (3.5 mL) at 0° C. was added acetyl chloride (0.8 mL) over 3 min.After stirring the solution for 1 h, the solution was added to 89C (69mg, 0.14 mmol) in CH₂Cl₂ (0.3 ml) at r.t. The mixture was stirred atr.t. for 2 h and then concentrated. The residue was dissolved in water,filtered through a 0.45μ nylon filter and lyophilized to give the titlecompound as a white amorphous solid. MS (M+H) 389, HPLC retention time2.92 min.

Example 90 (4-Hydroxy-butyl)-carbamic acid3-[1-(2-amino-2-methyl-propionylamino)-2-benzyloxy-ethyl]-imidazo[1,5-a]pyridin-5-ylmethylester

To a stirred solution of potassium phthalimide (1.04 g, 5.15 mmol) at RTunder argon in DMF (40 mL) was added a DMF solution (10 mL) of(6-bromomethylpyridin-2-yl)-methanol (1.03 g, 5.11 mmol) over 5 min. Theslurry was warmed at 40° C. and stirred overnight. The DMF was thendistilled off at 40-55° C. (1 Torr). The powdery residue was stirredrapidly in CH₂Cl₂ for 20 min and filtered through Celite. The residuewas redissolved in CH₂Cl₂, washed with water, dried and concentrated togive 90A as an off-white solid (1.16 g, 85%)

To a stirred solution of 90A (1.2 g, 4.32 mmol) in EtOH (60 ml) wasadded hydrazine (0.41 mL, 13.1 mmol) and the reaction mixture wasrefluxed for 14 h under argon. The solution was cooled, filtered throughCelite and the filtrate concentrated. The residue was redissolved inMeOH, cooled, filtered and concentrated to give(6-aminomethyl-pyridin-2-yl)-methanol. To a stirred solution ofBoc-(O-benzyl)serine (1.3 g, 4.32 mmol) and N-methyl morpholine (0.484mL, 4.4 mmol) in THF (10 mL) at −12° C. was added isobutylchloroformate(0.56 mL, 4.35 mmol). After 30 min stirring, a slurry of(6-aminomethylpyridin-2-yl)-methanol in THF was added over 1 min. Thesolution was stirred at r.t. for 1 h. The reaction was diluted withEtOAc, washed with saturated aqueous sodium bicarbonate solution, driedand concentrated to give 90B as a yellow oil (1.9 g). The material wasused without purification in the following reaction.

To a solution of 90B (1.9 g, 4.3 mmol) in DMF (10 ml) was addedimidazole (410 mg, 6.02 mmol) and t-butyldimethyl-silylchloride (750 mg,4.98 mmol). The solution was stirred for 20 h. The reaction was quenchedwith water, extracted with EtOAc, dried, filtered and concentrated.Purification by flash chromatography on silica gel (19:81 EtOAc/CH₂Cl₂as elutant) gave 90C (1.4 g, 53%) as a colorless oil.

To a stirred slurry of 90C (1.4 g, 2.6 mmol) and1,2-dibromo-1,1,2,2-tetrachloroethane (1.9 g, 5.8 mmol) in acetonitrile(15 mL) at 0° C. was added triphenylphosphine (1.5 g, 5.8 mmol) and TEA(1.60 mL, 11.6 mmol). After 30 min, the resulting yellow slurry wasstirred at r.t. for 16 h. A red solution had formed. This wasconcentrated, partitioned between water and EtOAc, dried, filtered andconcentrated. Purification by flash chromatography on silica gel (3:17EtOAc/CH₂Cl₂ as elutant) gave 90D as a tan oil (625 mg, 46%).

To MeOH (8 mL) at 0° C. was added acetyl chloride (2.0 mL) over 3 min.After stirring the solution for 1 h, it was added to 90D (620 mg, 1.2mmol) at 0° C. The solution was stirred for 2 h and concentrated. Theresidue was dissolved in CH₂Cl₂ (5 mL) and added to a stirred slurry ofBoc-2-aminoisobutyric acid (370 mg, 1.82 mmol), HOAt (249 mg, 1.82 mmol)and EDAC (346 mg, 1.82 mmol) followed by addition of N-methylmorpholine(0.3 mL, 2.7 mmol). The mixture was stirred for 15 h, diluted withCH₂Cl₂, washed with saturated aqueous NaHCO₃, dried and concentrated.Purification by flash chromatography on silica gel (3:17 EtOAc/CH₂Cl₂ aselutant) gave 90E as a colorless foam (450 mg, 77%).

To a solution of 90E (279 mg, 0.58 mmol) and pyridine (0.12 mL, 1.4mmol) in THF (3 m-L) 0° C. was added 4-nitrophenyl chloroformate (256mg, 1.3 mmol) in CH₂Cl₂ (3 mL). The solution was stirred for 1 h andconcentrated. The residue was dissolved in THF (5 mL) and 4-aminobutanol(0.5 mL) was added. The solution was stirred for 30 min, diluted withEtOAc, washed with 1N NaOH, dried and concentrated. Purification byflash chromatography on silica gel (EtOAc as elutant) gave 90F as ayellow oil (207 mg, 60%).

Example 90

To MeOH (8 mL) at 0° C. was added acetyl chloride (2.0 mL) over 3 min.After stirring the solution for 1 h, it was added to 90F (204 mg, 0.342mmol) at 0° C. The solution was stirred for 2 h and concentrated. Theresidue was lyophilized to give the title compound as a yellow solid. MS(M+H) 498, HPLC retention time 2.64 min.

The following compound has been synthesized utilizing the proceduresdescribed in Example 90, utilizing the appropriate starting materials.Example 263 was also prepared by this method. HPLC HPLC Compound MassPurity Retention number Structure M + H (%) (min) 91

584 98 2.6

Example 923-[1-(2-Amino-2-methyl-propionylamino)-2-benzyloxy-ethyl]-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylicacid benzyl ester

To a solution of 3-Oxo-piperazine-1-carboxylic acid benzyl ester (1.5 g,6.4 mmol) in CH₂Cl₂ (20 ml) was added trimethyloxonium tetrafluroborate(0.99 g, 6.72 mmol). The solution was stirred for 60 h. A solution of(2-Benzyloxy-1-hydrazinocarbonyl-ethyl)-carbamic acid tert-butyl ester(2.07 g, 309.7 mmol) in CH₂Cl₂ (20 ml) was added to give a clearsolution. After 2 h of stirring the solution was diluted with CH₂Cl₂,washed with water, dried and concentrated to give 92A as a white foam(3.2 g, 95%).

A solution of 92A (2.6 g, 4.9 mmol) in EtOH (26 ml) was treated bymicrowave at 120° C., 60 W for 10 min. The mixture was treated with4NHCl in dioxane (30 ml) for 30 min. The solution was concentrated andcoevaporated with ethanol to 92B (2.8 g).

To a CH₂Cl₂ (100 ml) solution of2-tert-butoxycarbonylamino-2-methyl-propionic acid (1.34 g, 66.1 mmol)was added EDAC (1.8 g, 9.45 mmol) and HOBT (1.27 g, 9.45 mmol), DMAP(0.77 g, 6.3 mmol), and TEA (2.63 ml, 18.9 mmol). This solution wasstirred at r.t. for 10 min before the addition of 92B (2.8 g, 6.3 mmol).The reaction was completed in 2 h. The solution was diluted with CH₂Cl₂,washed with water, 1HCl, 1N NaOH, dried and concentrated. Purificationby flash chromatography on silica gel (5:95 MeOH/CH₂Cl₂ as elutant) gave92C as a foam (3 g).

Example 92

To a solution of 92C (250 mg) in CH₂Cl₂ was treated with HCl (30 ml 4 MHCl in dioxane) and stirred at r.t for 1 h. The solution wasconcentrated and the residue crystallized using MeOH/EtOAc to give thetitle compound as a solid (130 mg). MS (M+H) 493, HPLC retention time2.33 min.

Example 933-[1-(2-Amino-2-methyl-propionylamino)-2-benzyloxy-ethyl]-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylicacid naphthalen-2-ylmethyl ester

To a solution of 92C (2.6 g, 4.4 mmol) and catalyst palladium on carbon(30 mg) in MeOH (70 ml) under nitrogen was added ammonium formate (1.3g, 20.9 mmol). The solution was stirred for 3 h and filtered throughcelite and concentrated to give 93A (2.45 g)

To a solution of 2-naphthalenmethanol (11 mg, 0.07 mmol) in CH₂Cl₂ (0.25ml) was added n-methylmorpholine (12 μl, 0.1 mmol) and 4-nitrophenylchloroformate (15 mg, 0.0735 mmol) in CH₂Cl₂ (0.25 ml). The solution wasstirred overnight followed by addition of 93A (32 mg, 0.07 mmol) inCH₂Cl₂ (0.08 ml) and TEA (0.1 ml, 0.7 mmol). The solution was stirredovernight and diluted with CH₂Cl₂, washed with 1NHCl, 1NaOH, water,dried and concentrated to give 93B.

Example 93

To a solution of 93B in CH₂Cl₂ was treated with TFA in CH₂Cl₂ andstirred at r.t for 1 h. The solution was concentrated. The residue waspurified by preparative HPLC to give the title compound. MS (M+H) 543,HPLC retention time 2.82 min.

The following compounds were synthesized utilizing the procedures asdescribed in Example 93, utilizing the appropriate starting materials asknow to those skilled in the art.

Compound number R Mass M + H HPLC Purity (%) HPLC Retention (min) 94

523 80 2.77 95

507 90 2.57 96

521 90 2.8 97

511 85 2.4 98

549 81 3.04 99

529 85 2.5 100

529 90 2.48 101

518 97 2.08 102

529 80 2.42 103

511 90 2.4 104

511 95 2.37 105

523 90 2.37 106

535 90 2.97

The following examples were prepared using procedures as described inthe general synthetic schemes and working examples above, utilizing theappropriate starting materials as know to those skilled in the art. HPLCHPLC Compound Mass Purity Retention number Structure M + H (%) (min) 107

437 92 2.5 108

420 90 1.71 109

416 98 1.9 110

433 96 1.8 111

459 90 1.9 112

448 85 2.3 113

390 2.7 99 114

473 88 2.24 115

416 100 1.9 116

459 90 1.87 117

486 100 1.23 118

434 93 2.6 119

455 99 4.04 120

469 97 2.73 121

368 92 1.5 122

450 95 2.2 123

407 98 2.2 124

447 95 2.05 125

413 95 1.9 126

469 90 2.52 127

493 2.98 128

398 90 2.26 129

412 98 2.71 130

499 97 2.6 131

483 85 3.1 132

473 95 2.4 133

399 93 1.7 134

502 94 135

409 86 1.14 136

446 99 2.3 137

370 95 2.07 138

431 99 2.3 139

380 90 140

432 97 2.2 141

413 95 2.4 142

467 93 2.9 143

467 97 2.86 144

521 89 2.8 145

521 85 2.96 146

457 100 2.9 147

417 85 1.37 148

445 90 1.95 149

520 95 3.2 150

520 90 3.26 151

458 97 2.4 152

445 90 2.22 153

359 90 0.4 154

463 95 1.81 155

539 95 2.9 156

445 95 2.08 157

463 95 2.17 158

477 85 1.95 159

397 98 1.5 160

397 94 1.13 161

385 95 162

412 100 1.6 163

499 95 2.03 164

549 94 2.56 165

379 98 1.5 166

497 96 2.58 167

499 96 2.85 168

471 95 2.43 169

485 95 2.5 170

513 94 2.7 171

368 98 1.21 172

491 95 2.21 173

447 97 2.8 174

467 95 2.8 175

400 95 2.34 176

453 90 2.37 177

369 98 2.58 178

499 95 1.75 179

485 90 1.6 180

423 97 5.80 181

506 94 3.2 182

465 100 2.8 183

430 88 2.4 184

463 94 3.4 185

414 94 2.23 186

414 94 2.23 187

413 97 2.6 188

535 90 2.62 189

535 95 2.8 190

519 96 2.88 191

563 90 2.76 192

563 90 2.87 193

442 98 2.5 194

497 98 195

485 98 196

384 95 1.67 197

527 90 2.64 198

527 84 2.56 199

535 98 2.5 200

535 95 2.8 201

563 98 2.68 202

563 98 2.9 203

519 90 2.86 204

519 90 2.94 205

444 90 1.77 206

448 95 6.04 207

432 98 2.94 208

483 90 2.53 209

459 90 2.25 210

512 95 2.36 211

470 98 3.07 212

495 100 2.82 213

512 100 2.87 214

499 100 2.87 215

482 100 2.78 216

532 100 2.92 217

475 95 1.61 218

505 85 2.41 219

528 90 2.62 220

521 90 2.32 221

527 90 2.49 222

521 90 2.7 223

561 90 2.63 224

547 90 2.9 225

499 94 2.4 226

404 95 1.45 227

507 92 2.5 228

499 100 3.05 229

499 100 3.06 230

507 97 2.51 231

495 94 2.9 232

495 95 2.9 233

463 97 2.85 234

482 93 2.85 235

482 99 2.85 236

500 97 2.9 237

509 97 3.06 238

557 92 3.4 239

495 87 2.68 240

559 98 3.4 241

489 80 2.6 242

508 90 2.85 243

383 90 1.96 244

383 88 2.19 245

527 96 2.8 246

584 90 2.44 247

500 98 2.94 248

514 100 3.1 249

566 94 3.28 250

455 98 2.55 251

507 82 2.2 252

370 95 1.38 253

411 96 5.19 254

415 95 4.67 255

543 91 2.76 256

569 94 2.88 257

521 93 2.74 258

575 98 2.79 259

575 92 2.74 260

507 90 2.43 261

496 98 2.62 262

471 98 2.38 263

499 95 2.58 264

515 98 2.50 265

531 92 2.62 266

547 92 2.93 267

525 98 2.84 268

525 96 2.76 269

511 99 2.73 270

511 98 2.62 271

501 95 2.83 272

523 96 2.93 273

398 93 1.90 274

477 95 2.41 275

394 95 2.57 276

429 94 4.73 277

491 95 2.17 278

412 95 2.07 279

541 95 3.13 280

555 95 3.18 281

555 95 3.13 282

542 90 2.16 283

556 90 2.22 284

556 90 2.22 285

460 95 2.54 286

525 90 2.07 287

521 90 2.72 288

601 90 3.34 289

539 90 2.85 290

581 90 3.33 291

507 90 2.42 292

383 97 1.47 293

359 100 0.22 294

518 95 2.80 295

485 93 2.61 296

413 91 1.39 297

426 100 2.59 298

437 98 2.11 299

532 80 2.50 300

532 100 2.64 301

540 93 2.89 302

477 86 1.89 303

540 95 3.01 304

498 82 2.37 305

475 75 2.30 306

475 85 2.30 307

425 99 1.56 308

455 93 1.86 309

395 90 1.73 310

409 93 1.82 311

500 96 2.64 312

495 96 2.78 313

510 98 2.92 314

475 89 1.99 315

495 95 2.79 316

525 96 2.92 317

437 100 2.11 318

467 97 1.37 319

439 98 2.26 320

468 98 1.13 321

465 94 1.90 322

487 99 2.57 323

480 83 0.73 324

411 99 1.74 325

524 96 2.56 326

574 95 2.93 327

498 93 1.64 328

568 95 3.05 329

602 93 3.08 330

372 80 1.75 331

423 98 1.14 332

371 90 2.14 333

414 83 2.29 334

485 93 2.25 335

497 98 2.63 336

490 98 3.01 337

529 98 3.01

Example 338

To a solution n-BuLi (2.5 M in THF, 84 ml, 0.21 mol) in toluene (200 mL)at −10° C. was added n-BuMgCl (2.0 M in THF, 52.5 ml, 0.105 mol) over 10min. The mixture was stirred at −10° C. for 30 min, then2,6-dibromopyridine (71.07 g, 0.3 mol) in toluene (500 mL) was added viaan additional funnel over 30 min. The resulting suspension was stirredat −10° C. for 2.5 hours, then transferred via a canula to a cooledsolution of DMF in toluene (200 mL). The solution was stirred at −10° C.for 30 min, then 30% citric acid (300 mL) was added. After stirring for30 min, the organic phase was washed with water (300 mL), brine (200mL), and dried over sodium sulfate. After filtratoin the filtrate wasconcentrated to give 338A as light yellow colored solid (54.2 g). HPLC(A) retention time 1.88 min.

To a stirred soln of 338A (29.0 g, 0.151 mol) in methanol (600 mL)cooled to 12° C. in a water bath is added sodium borohydride (5.89 g,0.16 mol) in small batches over 20 min. The temperature is not allowedto rise above 23° C. The reaction mixture was stirred 1 h more and thencautiously quenched with ice cold 10% HCl to pH2 (total of 64 mL). Thereaction mixture was concentrated in vacuo, generating considerablefoaming. The residue was redissolved in methylene chloride (250 mL) andstirred with a 5% potassium carbonate solution (150 mL, at pH 8). Theaqueos layer was extracted twice with methylene chloride (250 mL each).The combined organics were dried with sodium sulfate, filtered throughmagnesium sulfate, and concentrated in vacuo to give 338B as a yellowcolored oil, (27.65 g). The compound slowly crystallizes to a yellowcolored solid. MS (M+H+) 188, 190; HPLC (A) retention time 1.99 min.

To a stirred solution of 338B (25.0 g, 0.129 mol) in DMF (200 mL) atroom temperature under argon is added imidazole (17.56 g, 0.258 mol) andthen, after the imidazole had dissolved, tert-butyldimethylsilylchloridel (23.27 g, 0.155 mol) in one portion. A slight endotherm isnoted. After stirring for 16 h., the reaction mixture was quenched withice water (500 mL) and extracted 3×250 mL hexanes. The hexane extractswere combined, washed twice with water (150 mL) and once with brine.After drying the organics over sodium sulfate, they were filteredthrough magnesium sulfate, and stripped to give 338C as a light yellowcolored oil (39.15 g). MS (M+H) 302, 304; HPLC (A) retention time 4.56min.

A 1 L 3-necked flask is charged with a solution of 338C (38.5 g, 0.127mol) in pyridine (500 ml) and treated with hydrazine (40 ml, 1.28 mol)in one portion. A slight endotherm is noted. The reaction mixture isstirred and heated to reflux under argon (pot temperature 109-111° C.)for 45 h. After cooling to room temp in an ice bath, solid sodiumbicarbonate (11 g) is added. The mixture is stirred for 1 h and strippedto give a yellow oil. Addition of water (200 mL) leads to formation of asolid with the aid of seed crystals. The solid mass is broken up,collected, and washed with water (5×100 mL). In order to expeditedrying, the solid is dissolved in ether (500 mL), washed once withbrine, dried over sodium sulfate, and filtered through magnesiumsulfate. The organics were concentrated in vacuo to give 338D as anoff-white solid (31.5 g). MS (M+H+) 254; HPLC (A) retention time 2.53min.

A 1 L 3-necked flask (oven-dried) is charged withN-(tert-butoxycarbonyl)-D-serine (35.74 g, 0.12 mol) in THF (250 mL) andcooled to −13° C. (isopropanol/ice bath) under argon. N-Methylmorpholine(13.74 ml, 0.125 mol) is added in one portion (temperature temporarilyrises to 2° C.). After the temperature cools again to −13° C.,isobutylchloroformate (15.69 ml, 0.12 mol) is added at such a rate as tokeep the temperature below −10° C. The reaction mixture is stirred 20min and then a solution of 338D (30.4 g, 0.12 mol) in THF (100 mL) isadded over 15 min, not allowing the temperature to rise above −5.5° C.during this addition process. The addition funnel is rinsed with THF (25mL) and the yellow reaction slurry is stirred for 90 min. The reactionis quenched at −10° C. with saturated sodium bicarbonate (100 mL) andthe aqueous layer is extracted twice with ethyl acetate (500 mL). Thecombined organics were washed once with brine, 10% citric acid,saturated sodium bicarbonate, and dried over sodium sulfate. Afterfiltering through magnesium sulfate, the volatiles were removed invacuo, and the residue restripped from methylene chloride/hexanes togive 338E as a yellow foam (63.97 g). MS (M+H+) 531; HPLC (A) retentiontime 3.91 min.

To a stirred solution of 338E (93.6 g, 0.177 mol) in THF (800 mL) at−78° C. under nitrogen is added triethylamine (196 ml, 1.41 mol). After10 min, dichlorotriphenylphosphine (194.2 g, 0.583 mol) is added portionwise over 10 min. The mixture was stirred and slowly warmed to roomtemperature overnight (−20 h). The volatiles were removed and theresidue was filtered through a short silicon gel column, rinsing thecolumn with hexane/ethyl acetate (1:2). The combined filtrates wereevaporated to give the crude 338F (200 g, mixed with triphenylphosphineoxide). MS: (M+H+) 513; HPLC (A) retention time 4.30 min.

An alternative procedure: To a stirred solution of 338E (63.95 g, 0.12mol) in THF (800 ml) at −73° C. under argon is added triethylamine (134ml, 0.964 mol). After 15 min, dichlorotriphenylphosphine (132.49 g,0.398 mol) is added portion wise over 30 min, stirred 1 h and thenbrought to −10° C. by displacing the acetone cold bath with roomtemperature water. The reaction mixture is allowed to warm from −10° C.to room temperature in situ overnight, then filtered through Celite andconcentrated in vacuo. The resulting solid was dissolved in methylenechlroide (750 mL), cooled to 0° C. and treated with ice-cold 10% citricacid (100 mL). The mixture was stirred rapidly for 5 min, the organicswashed once with water, saturated sodium bicarbonate, dried (magnesiumsulfate), filtered and restripped to give 338F as a light tan coloredsolid (167.74 g, contaminated with triphenylphosphine oxide).

To methanol (400 ml) at 2° C. was added acetyl chloride (100 g) dropwiseover 20 min. After stirring 30 min, the solution was brought to roomtemperature for 45 min. The methanol solution was added directly tocrude 338F (<167 g, 0.12 mol) and the mixture was stirred for 3 h,concentrated in vacuo at temperatures below 30° C., and then the browncolored residue was suspended in THF (500 mL) for 30 min. The resultingsolid was collected by filtration, and re-suspended in THF (500 mL) for30 min. After filtration, the solid was dried in vacuo at 40° C. to give338G as light yellow colored solid (38.6 g). MS (M+H) 299; HPLC (A)retention time 1.65 min.

To a stirred slurry of N-(tert-butoxycarbonyl)-α-methylalanine (24.39 g,0.120 mol) and HOBt (18.37 g, 0.120 mol) in methylene chloride at roomtemperature under argon is added EDAC (22.83 g, 0.120 mol) as a solidover 10 min. The resulting solution is stirred 1 h and then added(filtering through a cotton plug) to a solution of 338G (−0.120 mol) andN-methylmorpholine (19.79 ml, 0.18 mol) in methylene chloride at roomtemperature. After stirring 45 h, the reaction mixture was stirred withsaturated sodium bicarbonate (200 mL) for 30 min. The phases wereseparated and the organic extract was washed once with brine, 10% citricacid (at pH3) and once again with brine. The organics were dried oversodium sulfate, filtered, and the filtrate was partially evaporated (to˜250 mL volume) and ether (−100 mL) was added. The resulting solids werefiltered to give 338H as a colorless solid (30.10. The mother liquorswere concentrated and recrystallized from chloroform (50 mL) and hexanes(sufficient to cause cloudiness in the boiling solution) to obtain anadditional 3.45 g. Both solids were combined to give 338H (33.55 g). mp155-157 deg° C. MS (M+H+) 484; HPLC (A) retention time 2.85 min.

To a suspension of 338H (25.63 g, 0.053 mol) in methylene chloride (300mL) at 0° C. was added pyridine (9.0 mL, 0.111 mol). After 10 min,para-nitrophenyl chloroformate (21.4 g, 0.106 mol) was added slowlyunder nitrogen and the reaction was slowly warmed to room temperatureovernight. The mixture was filtered and the solid cake was rinsed withmethylene chloride (100 mL). The filtrate was concentrated in vacuo,ethyl acetate and ether (200 mL, 1:1) were added and the mixture wasstirred at room temperature for 30 min. The solids were filtered and thecrude solid product was collected. The solid was re-suspended in ethylacetate and ether (200 mL, 1:1) three times to give 3381 as a colorlesssolid (38.5 g). MS (M+H+) 649; HPLC (A) retention time 3.68 min.

To a suspension of sarcosinamide (2.61 g, 29.6 mmol) in anhydrous THF(250 mL) at 2° C. was added solid 3381 (16.0 g, 24.7 mmol) over 10 min.The yellow mixture was stirred at room temperature for 24 h. Afterconcentration, the resulting yellow foamy residue was diluted with ethylacetate (600 mL) and washed with cold 1N NaOH (7×100 ml), water (100 ml)and dried over magnesium sulfate. The organic layer was concentrated invacuo to give crude 338J as colorless solid (14.38 g). The materialcould be further purified by column chromatography, eluting with 10%methanol/methylene chloride to give pure 338J (10.47 g). MS (M+H+) 531;HPLC (A) retention time 3.91 min.

Example 338

HCl gas (67.8 g, 1.86 mol) was bubbled into ice-cold isopropanol (200mL). The resulting solution was cooled to 5° C. and solid 338J (13.8 g,23.1 mmol) was added in portions over 5 min. After 30 min at 0° C., thereaction mixture was stirred at room temperature an additional 30 minbefore concentration in vacuo. The resulting viscous liquid was stirredwith isopropanol (100 mL) and the resulting colorless solid wascollected by filtration to give 338 (12.65 g). mp 151.4-152.6° C.; MS(M+H+) 498; HPLC (A) retention time 1.723 min.

Example 339

To a stirred slurry of intermediate 3381 (37.41 g, 0.058 mol) andtriethylamine (12.06 ml, 0.087 mol) in THF (300 ml) at room temperatureunder argon was added morpholine (5.53 ml, 0.063 mol) over 2 minutes. Ayellow solution forms within 5 min and the reaction was stirredovernight. After 15 h, the reaction solution was concentrated in vacuoand re-dissolved in EtOAc (800 mL). The organic layer was washed withsaturated sodium bicarbonate (5×125 mL), once with 5% potassiumhydrogensulfate (200 mL), brine and once with saturated sodiumbicarbonate (100 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated to give a colorless foam, 37.5 g.This material is recrystallized twice from 5:4 ethyl acetate:hexane togive 339A as a colorless solid (30.95 g). mp 104-106° C., MS (M+H+) 597;HPLC (A) retention time 3.58 min.

Acetyl chloride (50 ml, 0.637 mol) was added dropwise over 30 min to drymethanol (200 mL) at 0° C. After 30 min, the mixture was warmed to roomtemperature, stirred 1 h, then added to solid 339A (30.2 g, 0.051 mol).After 4 h, the reaction mixture was concentrated and the resultingcolorless amorphous solid was suspended in THF and sonicated for 30 min.Filtration gave a colorless amorphous solid which was dried at 45° C.for 15 h to give 339 (25.75 g). MS (M+H) 497; HPLC (A) retention time2.73 min. CHN elemental analysis: C25H32N6O{tilde over (5)}2HCl

The following examples were prepared using procedures as described inthe general synthetic schemes and working examples above, utilizing theappropriate starting materials as known to those skilled in the art.HPLC HPLC Compound Mass Purity Retention number Structure M + H (%)(min) 340

512 95 1.73 341

511 95 2.07 342

524 96 2.56 343

455 95 3.33 344

534 97 1.85 345

533 98 2.3 346

523 96 4.10 347

497 97 4.73 348

534 97 4.73

The following examples were prepared using procedures as described inthe general synthetic schemes and working examples above, utilizing theappropriate starting materials as known to those skilled in the art.HPLC HPLC Compound Mass Purity Retention number Structure M + H (%)(min) 349

414 94 2.67 350

437 97 2.13 351

384 99 1.28 352

538 95 2.53 353

552 92 2.70 354

510 92 2.47 355

434 99 2.60 356

526 95 2.60 357

512 95 2.54 358

594 95 3.07 359

538 95 2.68 360

552 95 2.64 361

568 95 3.06 362

495 97 2.35 363

561 90 2.28 364

483 98 2.36 365

384 95 1.96 366

512 95 2.48 367

538 95 2.63 368

511 95 2.71 369

497 95 2.63 370

511 95 2.74 371

497 98 1.87 372

499 95 2.13 373

524 95 1.73 374

521 90 1.77 375

528 98 2.93 376

500 95 1.85 377

452 90 1.78 378

465 95 2.15 379

461 95 1.47 380

404 96 2.74 381

404 97 2.65 382

430 98 2.77 383

513 95 3.12 384

545 95 2.49 385

485 92 2.56 386

485 93 2.55 387

510 92 2.42 388

460 100 2.87 389

372 80 1.51/1.64 390

495 95 3.19 391

499 95 2.86 392

523 95 2.97 393

499 93 2.99 394

499 95 2.81 395

499 95 2.75 396

481 95 3.01 397

523 93 2.20 398

524 97 1.89 399

516 99 2.21 400

533 100 2.40 401

481 95 3.52 402

483 95 3.72 403

469 95 3.59 404

483 95 2.56 405

497 90 2.74 406

483 90 2.56 407

479 90 2.28 408

479 92 1.57 409

507 99 2.04 410

393 98 4.84 411

461 89 2.32 412

502 96 2.34 413

567 90 3.78 414

549 90 3.60 415

499 90 3.08 416

441 90 2.64 417

455 90 2.91 418

454 93 2.37 419

496 94 2.03 420

456 93 2.44 421

408 95 1.87 422

393 97 4.93 423

480 75 2.01 424

494 80 2.00 425

466 80 1.80 426

495 97 1.62 427

495 98 2.31 428

495 98 2.31 429

497 95 2.17 430

467 90 2.00 431

455 93 2.43 432

495 98 2.06 433

469 98 2.07 434

512 90 1.94 435

402 95 2.12 436

533 99 4.18 437

509 98 3.02 438

533 98 4.13 439

562 98 1.98 440

534 96 1.96 441

523 98 3.08 442

496 85 1.45 443

512 96 1.89 444

497 95 2.09 445

498 97 1.75 446

548 98 1.89 447

524 96 1.88 448

521 97 1.38 449

454 96 1.39 450

535 95 1.34 451

538 92 2.26 452

526 94 2.11 453

512 90 2.04 454

512 94 2.02 455

493 98 2.62 456

536 98 2.20 457

535 98 2.19 458

510 90 2.40 459

521 97 460

511 99 3.11 461

512 99 2.76 462

536 96 2.92 463

499 96 2.07 464

461 97 1.58 465

512 89 1.65 466

504 92 2.33 467

503 92 2.66 468

553 94 2.16 469

523 89 1.69 470

469 97 5.71 471

511 97 5.53 472

512 97 4.97 473

526 99 2.09 474

511 98 2.55 475

512 97 2.18 476

469 97 2.62 477

425 97 1.43 478

533 95 2.03 479

512 95 1.71 480

496 95 1.96 481

496 98 1.96 482

435 96 4.41 483

449 99 4.66 484

555 92 3.14 485

555 92 3.12 486

556 92 2.86 487

556 93 2.88 488

493 99 2.26 489

494 99 1.92 490

498 96 1.41 491

497 89 1.79 492

490 99 1.92 493

532 99 1.94 494

485 97 5.83 495

532 99 5.69 496

533 98 5.07 497

518 96 1.97 498

517 90 2.25 499

516 90 2.37 500

515 95 2.68 501

484 95 1.69 502

544 95 2.79 503

543 92 3.01 504

576 96 2.44 505

577 88 2.13 506

427 90 1.76 507

460 100 2.56 508

464 95 1.84 509

525 91 1.59 510

524 90 1.96 511

511 94 2.21 512

540 98 4.73 513

511 99 3.28 514

512 94 2.91 515

538 97 3.10 516

539 99 5.35 517

461 95 0.197/0.97 518

499 99 2.03 519

573 97 2.79 520

574 95 2.58 521

574 93 1.59 522

575 95 0.197/1.21 523

520 95 2.80 524

519 95 3.00 525

490 95 2.00 526

489 95 2.40 527

504 95 2.16 528

503 95 2.45 529

478 92 2.03 530

477 93 2.39 531

384 97 3.21 532

411 98 2.74 533

393 98 3.85 534

513 95 2.17 535

517 95 2.67 536

518 97 2.38 537

544 95 2.47 538

498 92 1.71 539

489 95 3.05 540

490 97 2.67 541

516 97 2.83 542

513 95 2.31 543

514 99 1.87 544

512 90 3.80

The following examples were prepared using procedures as described inExample 90, as well as described in the general synthetic schemes andworking examples above, utilizing the appropriate starting materials asknown to those skilled in the art. HPLC HPLC Compound Mass PurityRetention number Structure M + H (%) (min) 545

378 97 3.03 546

496 94 5.67 547

520 94 5.08 548

498 99 5.88 549

523 96 4.10 550

494 98 6.78 551

497 91 4.73 552

496 95 5.19 553

542 96 7.27 554

510 97 3.10 555

510 96 2.85 556

511 98 2.84 557

537 98 2.84 558

521 98 3.56 559

522 97 3.38 560

573 98 2.75 561

572 98 2.97 562

599 97 2.80

The following examples were prepared using procedures as described inExample 92 and Example 93 above, and as described in the generalsynthetic schemes and working examples above, utilizing the appropriatestarting materials as known to those skilled in the art. Compound MassHPLC HPLC Retention number Structure M + H Purity (%) (min) 563

583 95 3.09 564

529 95 3.10 565

572 95 3.20 566

575 90 2.61 567

557 84 3.42 568

499 95 2.77 569

575 95 3.40 570

529 97 3.21 571

509 98 2.89 572

516 93 0.19 573

612 95 2.89 574

600 95 2.70 575

536 95 2.60 576

518 95 2.93 577

573 99 2.62 578

560 98 3.43 579

532 95 2.64 580

586 97 3.20 581

545 98 582

586 95 1.99 583

574 99 584

537 90 3.64 585

575 95 2.79 586

575 95 2.80 587

514 97 1.84 588

557 95 2.84 589

494 97 2.85 590

590 98 2.37 591

515 90 2.68

The following examples were prepared using procedures as described inthe general synthetic schemes and working examples above, utilizing theappropriate starting materials as known to those skilled in the art.HPLC Compound Purity HPLC Retention number Structure Mass M + H (%)(min) 592

461 94 3.01 593

503 95 2.39 594

385 95 1.26 595

461 96 2.52 596

371 90 1.26 597

461 97 2.43 598

385 90 1.47 599

503 97 2.00 600

503 98 2.21 601

502 96 2.66 602

504 91 603

530 95 604

530 91 605

490 90 606

461 91 607

372 97 3.03 608

501 98 3.28 609

553 95 610

554 90 611

504 96 1.77 612

518 96 1.85 613

546 90 1.87 614

544 96 2.20 615

505 95 2.26 616

519 95 2.54 617

487 95 618

488 90

The following pro-drug examples were prepared using procedures asdescribed in the general synthetic schemes and working examples above,utilizing the appropriate starting materials as known to those skilledin the art. HPLC Compound Purity HPLC Retention number Structure MassM + H (%) (min) 619

539 99 3.27 620

526 92 2.11 621

540 92 2.12 622

628 94 1.81 623

570 94 2.08 624

654 99 3.46

1. A compound of the formula I

wherein R₁ is a substituted or unsubstituted alkyl; R₂ is a substitutedor unsubstituted functional group selected from the group consisting ofhydrogen, alkyl, aryl, alkenyl, alkynyl, arylalkyl, cycloalkyl,heterocycle, alkoxyalkyl, arylalkyloxyalkyl, aryloxyalkyl, heteroaryl,cycloalkylalkoxyalkyl, heteroarylalkyl and hetercycloalkyl; R₃ and R₄are each independently a substituted or unsubstituted functional groupselected from the group consisting of hydrogen and alkyl, or R₃ and R₄taken together can form a 4 to 7 membered heterocyclic ring, or one ormore of R₃ and R₄ can be taken together with Y to form a 4 to 7 memberedheterocyclic ring; R₁′ is a substituted or unsubstituted functionalgroup selected from the group consisting of hydrogen, alkyl, cycloalkyl,heterocycle, aryl and heteroaryl; Y is a linking group selected from thegroup consisting of alkylene, alkenylene, alkynylene, arylene andheteroarylene, said linking group may optionally be substituted with oneor more functional group selected from the group consisting of alkyl,aryl, cycloalkyl, heterocycle, alkoxyalkyl, heteroaryl, arylalkyl,arylalkyloxyalkyl, aryloxyalkyl, cycloalkylalkoxyalkyl, heteroarylalkyl,—OR₅, —OC(O)R₅, —CF₃, —OCF₃, —N(R₅)C(O)R₅′ and —NR₅R₅′; R₅ and R₅′ foreach occurrence are each independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, heterocycle and aryl, whereinR₅ and R₅′ for each occurrence may optionally be substituted with one ormore Rb; Ra and Rb for each occurrence are each independently selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,cyano, —CN, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl,alkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl, heterocycle, heteroaryl,heteroarylalkyl, —OR₂, —NR₅R₅′, —CF₃, —SO₂R₆, —OC(O)R₅—SO₂NR₆R₆′,—(CH₂)_(m)R₈ and R₉; R₆ and R₆′ for each occurrence are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, alkylthioalkyl, alkoxyalkyl, aryl, arylalkyl,heterocycle, heteroaryl, heteroarylalkyl, heterocycloalkyl andcycloalkyl, wherein R₆ and R₆′ for each occurance may optionally besubstituted with 1 to 3 substituents selected from the group consistingof halogen, OR₂, alkoxy, heterocycloalkyl, —NR₅C(O)NR₅R₅′, —C(O)NR₅R₅′,—NR₅C(O)R₅′, —CN, —NR₅SO₂R₅′, —OC(O)R₅, —SO₂NR₅R₅′, —SOR₇, —COOH and—C(O)OR₇, or R₆ and R₆′ taken together can be cyclized to form—(CH₂)_(q)X(CH₂)_(s)—; R₇ for each occurrence is independently selectedfrom the group consisting of C₁ to C₆ alkyl, aryl and heteroaryl,wherein R₇ may optionally be substituted with —(CH₂)_(w)OH; R₈ isselected from the group consisting of alkoxy, alkoxycarbonyl,—C(O)NR₆R₆′, —NR₅R₅′, —C(O)R₆, —NR₅C(O)NR₅R₅′ and —N-heteroaryl; R₉ isselected from the group consisting of heterocycloalkyl, heteroaryl, —CN,—(CH₂)_(p)N(R₆)C(O)R₆′, —(CH₂)_(p)CN, —(CH₂)_(p)N(R₆)C(O)OR₆′,—(CH₂)_(p)N(R₆)C(O)NR₆R₆′, —(CH₂)_(p)N(R₆)SO₂R₆, —(CH₂)_(p)C(O)NR₆R₆′,—(CH₂)_(p)C(O)OR₆, —(CH₂)_(p)OC(O)OR₆, —(CH₂)_(p)OC(O)R₆,—(CH₂)_(p)OC(O)NR₆R₆′, —(CH₂)_(p)N(R₆)SO₂NR₆R₆′, —(CH₂)_(p)OR₆,—(CH₂)_(p)OC(O)N(R₆)(CH₂)_(m)OH, —(CH₂)_(p)SOR₆ and—(CH₂)_(p)OCH₂C(O)N(R₆)(CH₂)_(m)OH; X is selected from the groupconsisting of —CR₅R₅′—, —O—, —S—, —SO—, —SO₂—, —NC(O)OR₇—, —NC(O)NR₅—and —NR₅—; m is an integer between 1 and 6; p is an integer from 0 to 5;w is an integer between 0 and 5; and q and s are each independently aninteger between 1 and 3, with the proviso that R₅, R₅′, R₆ or R₆′ cannotbe hydrogen when either is connected to a carbonyl group or sulfonegroup.
 2. The compound as defined in claim 1 wherein when Rb is R₉, R₆is heterocycle or alkyl, optionally substituted with hydroxyl orhalogen.
 3. The compound as defined in claim 2 wherein R₉ is(CH₂)_(p)C(O)OR, (CH₂)_(p)OC(O)R₆, or (CH₂)_(p)OC(O)N(R₆)(CH₂)_(m)OH. 4.The compound as defined in claim 1 wherein when Rb is R₉, R₆ and R₆′ areindependently hydrogen, alkyl, or cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with —C(O)OR₇ or —C(O)NR₅R₅′, or R₆and R₆′ taken together can be cyclized to form —(CH₂)_(q)X(CH₂)_(s)—. 5.The compound as defined in claim 4 wherein R₉ is—(CH₂)_(p)N(R₆)C(O)OR₆′, —(CH₂)_(p)N(R₆)C(O)NR₆R₆′, or(CH₂)_(p)OC(O)NR₆R₆′, where R₆ and R₆′ are independently hydrogen oralkyl, where the alkyl is optionally substituted with —C(O)NR₅R₅′, whereR₅ and R₅′ are independently hydrogen or alkyl.
 6. The compound asdefined in claim 1 wherein the compound has the structure:


7. The compound as defined in claim 1 wherein the compound has thestructure:


8. A pharmaceutical composition comprising a compound as defined inclaim 1 and a pharmaceutically acceptable carrier therefor.
 9. Thepharmaceutical composition of claim 8 further comprising at least oneadditional therapeutic agent selected from the group consisting of othercompounds of formula I, parathyroid hormone, bisphosphonates, estrogen,testosterone, selective estrogen receptor modulators, selective androgenreceptor modulators, progestin receptor agonists, anti-diabetic agents,anti-hypertensive agents, anti-inflammatory agents, anti-osteoporosisagents, anti-obesity agents, cardiac glycosides, cholesterol loweringagents and thyroid mimetics.
 10. The pharmaceutical composition of claim8 further comprising at least one nutritional supplement.
 11. A methodfor increasing levels of endogenous growth hormone, which comprisesadministering a therapeutically effective amount of a compound asdefined in claim 1 to a patient in need thereof.
 12. A method fortreating or delaying the progression or onset of HIV wasting syndrome,muscular atrophy, lipodistrophy, long term critical illness,osteoporosis, sarcopenia, fraility or ARFD in the elderly, obesity,renal disease, anorexia, sleep disorders, depression, Syndrome X,diabetes, congestive heart failure, cardiac myopathy, cardiacdysfunction associated with valvular disease and cachexia whichcomprises administering to a mammalian patient in need of treatment atherapeutically effective amount of a compound as defined in claim 1.13. The method according to claim 11 further comprising administering,concurrently or sequentially, a therapeutically effective amount of atleast one additional therapeutic agent selected from the groupconsisting of other compounds of formula I, parathyroid hormone,bisphosphonates, estrogen, testosterone, selective estrogen receptormodulators, selective androgen receptor modulators, progestin receptoragonists, anti-diabetic agents, anti-hypertensive agents,anti-inflammatory agents, anti-osteoporosis agents, anti-obesity agents,cardiac glycosides, cholesterol lowering agents and thyroid mimetics.14. A method for stimulating wound healing and/or the immune systemwhich comprises administering a therapeutically effective amount of acompound as defined in claim 1 to a patient in need thereof.
 15. Amethod for increasing muscle mass and/or strength or maintaining musclestrength and function in the elderly which comprises administering atherapeutically effective amount of a compound as defined in claim 1 toa patient in need thereof.
 16. A method of increasing lean body masswhich comprises administering a therapeutically effective amount of acompound as defined in claim 1 to a patient in need thereof.
 17. Amethod for improving cognitive function which comprises administering atherapeutically effective amount of a compound as defined in claim 1 toa patient in need thereof.
 18. A method for improving the immuneresponse to vaccination which comprises administering a therapeuticallyeffective amount of a compound as defined in claim 1 to a patient inneed thereof.
 19. A method for accelerating the recovery of hip fracturewhich comprises administering a therapeutically effective amount of acompound as defined in claim 1 to a patient in need thereof.